Bromodomain inhibitors

ABSTRACT

The present invention relates to substituted heterocyclic derivative compounds, compositions comprising said compounds, and the use of said compounds and compositions for epigenetic regulation by inhibition of bromodomain-mediated recognition of acetyl lysine regions of proteins, such as histones. Said compositions and methods are useful for the treatment of cancer and neoplastic disease.

CROSS REFERENCE

This application is a continuation of U.S. application Ser. No.14/789,881, filed Jul. 1, 2015, which is a continuation of U.S. patentapplication Ser. No. 14/658,048, filed Mar. 13, 2015 (now U.S. Pat. No.9,115,114, issued on Aug. 25, 201)5, which is a continuation of Ser. No.14/517,705, filed Oct. 17, 2014 (now U.S. Pat. No. 9,034,900, issued onMay 19, 2015), which claims the benefit of U.S. Provisional ApplicationsNo. 61/893,133, filed Oct. 18, 2013, and No. 61/931,467, filed Jan. 24,2014, the contents of which are hereby incorporated by reference intheir entireties for all purposes.

BACKGROUND

A need exists in the art for an effective treatment of cancer andneoplastic disease.

BRIEF SUMMARY OF THE INVENTION

Provided herein are substituted heterocyclic derivative compounds andpharmaceutical compositions comprising said compounds. The subjectcompounds and compositions are useful for epigenetic regulation byinhibition of bromodomain-mediated recognition of acetyl lysine regionsof proteins, such as histones. Furthermore, the subject compounds andcompositions are useful for the treatment of cancer, such as NUT midlinecarcinoma, Burkitts lymphoma, prostate cancer, breast cancer, bladdercancer, lung cancer and/or melanoma and the like. The substitutedheterocyclic derivative compounds described herein are based uponisoquinolinones and related heterocyclic structures. Saidisoquinolinones and related heterocyclic structures are substituted atthe 4-position with a group such as an aryl, a heteroaryl and the like,and on the nitrogen atom of the isoquinolinone or related heterocyclicstructure with a small alkyl group, such as a methyl group.

One embodiment provides a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof,

-   -   wherein,    -   R² is selected from CH₃, CH₂CH₃, CH₂CF₃, CH₂F, CHF₂, CF₃, CH₂D,        CHD₂, or CD₃;    -   X5 is C—R⁵ or N;    -   X6 is C—R⁶ or N;    -   X7 is C—R⁷ or N;    -   X8 is C—R⁸ or N; wherein no more than two of X5, X6, X7, or X8        may be N;    -   R⁵ is hydrogen, halogen, —OH, —CN, —OR⁶¹, —NHR⁶¹, —N(R⁶¹)₂,        alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,        heterocyclylalkyl, heteroaryl, or heteroarylalkyl, wherein each        R⁶¹ is independently selected from alkyl, cycloalkyl,        cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,        heteroaryl, or heteroarylalkyl;    -   R⁶ is hydrogen, halogen, —OH, —CN, —OR⁶¹, —NHR⁶¹, —N(R⁶¹)₂,        alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,        heterocyclylalkyl, heteroaryl, or heteroarylalkyl, wherein each        R⁶¹ is independently selected from alkyl, cycloalkyl,        cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,        heteroaryl, or heteroarylalkyl;    -   R⁷ is hydrogen, halogen, —OH, —CN, —OR⁶¹, —NHR⁶¹, —N(R⁶¹)₂,        alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,        heterocyclylalkyl, heteroaryl, or heteroarylalkyl, wherein each        R⁶¹ is independently selected from alkyl, cycloalkyl,        cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,        heteroaryl, or heteroarylalkyl;    -   R⁸ is hydrogen, halogen, or alkyl;    -   R^(A) is

-   -   X2 is N or C—R¹², wherein R¹² is hydrogen, halogen, alkyl, or        alkoxy;    -   R¹³ is —Y—Z;    -   Y is selected from a bond, —CH₂—, —CH(C₁-C₄ alkyl)-;    -   Z is selected from —SO₂R²¹, —N(R²²)SO₂R²¹, —SO₂N(R²²)₂,        —N(R²²)SO₂N(R²²)₂, —CON(R²²)₂, —N(R²²)CO₂R²¹, —N(R²²)CON(R²²)₂,        —N(R²²)COR²¹, —COR²¹, —OC(O)N(R²²)₂, —OSO₂N(R²²)₂, or        —N(R²²)SO₃R²¹;    -   X3 is N or C—R¹⁴, wherein R¹⁴ is hydrogen, halogen, —CN, alkyl,        cycloalkyl, or alkoxy;    -   X4 is N or C—R¹⁵, wherein R¹⁵ is hydrogen, halogen, alkyl, —CN,        or alkoxy;    -   R¹⁶ is hydrogen, halogen, or —W—X, wherein W is a bond, —O—,        —S—, or —NH—, and X is selected from alkyl, aryl, aralkyl,        cycloalkyl, cycloalkylalkyl, alkynyl, cycloalkylalkynyl,        heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;    -   each R²¹ is independently selected from alkyl, cycloalkyl,        cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,        heteroaryl, or heteroarylalkyl; and    -   each R²² is independently selected from hydrogen, alkyl,        cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,        heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

One embodiment provides a compound of Formula (II), or apharmaceutically acceptable salt thereof,

wherein,

-   -   R² is alkyl, cycloalkyl, cycloalkylalkyl, heterocyclylalkyl,        aralkyl, or heteroarylalkyl;    -   X6 is C—H or N;    -   X5 is C—R⁵ or N; provided that if X6 is N, then X5 is C—R⁵, and        if X5 is N, then X6 is CH;    -   R⁵ is hydrogen, halogen, —OH, —CN, —OR⁶¹, —NHR⁶¹, —N(R⁶¹)₂,        alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,        heterocyclylalkyl, heteroaryl, or heteroarylalkyl, wherein each        R⁶¹ is independently selected from alkyl, cycloalkyl,        cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,        heteroaryl, or heteroarylalkyl;    -   R⁶ is hydrogen, halogen, —OH, —CN, alkyl, cycloalkyl,        cycloalkylalkyl, amino, alkylamino, dialkylamino,        cycloalkylalkylamino, alkoxy, —S-alkyl, cycloalkylalkoxy,        heterocyclyl, aralkoxy, heteroaryloxy, aryloxy, alkynyloxy, or        —N(H)COalkyl;    -   R^(A) is

-   -   X2 is N or C—R¹², wherein R¹² is hydrogen, halogen, alkyl, or        alkoxy;    -   R¹³ is —Y—Z;    -   Y is selected from a bond, —CH₂—, or —CH(C₁-C₄alkyl)-;    -   Z is selected from —SO₂R²¹, —N(R²²)SO₂R²¹, —SO₂N(R²²)₂,        —N(R²²)SO₂N(R²²)₂, —CON(R²²)₂, —N(R²²)CO₂R²¹, —N(R²²)CON(R²²)₂,        —N(R²²)COR²¹, —COR²¹, —OC(O)N(R²²)₂, —OSO₂N(R²²)₂, or        —N(R²²)SO₃R²¹;    -   X3 is N or C—R¹⁴, wherein R¹⁴ is hydrogen, halogen, —CN, alkyl,        cycloalkyl, or alkoxy;    -   X4 is N or C—R¹⁵, wherein R¹⁵ is hydrogen, halogen, —CN, alkyl,        alkoxy, aryloxy, aralkyloxy, cycloalkylalkyloxy,        heterocyclyloxy, heteroarylalkyloxy, or alkynyloxy;    -   R¹⁶ is hydrogen, halogen, —N(H)COX, or —W—X, wherein W is a        bond, —O—, —S—, or —NH—, and X is selected from alkyl, aryl,        aralkyl, cycloalkyl, cycloalkylalkyl, alkynyl,        cycloalkylalkynyl, heterocyclyl, heterocyclylalkyl, heteroaryl,        or heteroarylalkyl;    -   each R²¹ is independently selected from alkyl, cycloalkyl,        cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,        heteroaryl, or heteroarylalkyl; and    -   each R²² is independently selected from hydrogen, alkyl,        cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,        heterocyclylalkyl, heteroaryl, or heteroarylalkyl; and    -   provided that when X6 is N, then R⁵ and R⁶ are not hydrogen.

One embodiment provides a pharmaceutical composition comprising acompound of Formula (I), or a pharmaceutically acceptable salt thereof,and a pharmaceutically acceptable excipient. One embodiment provides apharmaceutical composition comprising a compound of Formula (II), or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable excipient.

One embodiment provides a method of treating cancer in a patient in needthereof, comprising administering to the patient a compound of Formula(I), or a pharmaceutically acceptable salt thereof. One embodimentprovides a method of treating cancer in a patient in need thereof,comprising administering to the patient a compound of Formula (II), or apharmaceutically acceptable salt thereof.

INCORPORATION BY REFERENCE

All publications, patents, and patent applications mentioned in thisspecification are herein incorporated by reference to the same extent asif each individual publication, patent, or patent application wasspecifically and individually indicated to be incorporated by reference.

DETAILED DESCRIPTION OF THE INVENTION

As used herein and in the appended claims, the singular forms “a,”“and,” and “the” include plural referents unless the context clearlydictates otherwise. Thus, for example, reference to “an agent” includesa plurality of such agents, and reference to “the cell” includesreference to one or more cells (or to a plurality of cells) andequivalents thereof known to those skilled in the art, and so forth.When ranges are used herein for physical properties, such as molecularweight, or chemical properties, such as chemical formulae, allcombinations and subcombinations of ranges and specific embodimentstherein are intended to be included. The term “about” when referring toa number or a numerical range means that the number or numerical rangereferred to is an approximation within experimental variability (orwithin statistical experimental error), and thus the number or numericalrange may vary between 1% and 15% of the stated number or numericalrange. The term “comprising” (and related terms such as “comprise” or“comprises” or “having” or “including”) is not intended to exclude thatin other certain embodiments, for example, an embodiment of anycomposition of matter, composition, method, or process, or the like,described herein, may “consist of” or “consist essentially of” thedescribed features.

DEFINITIONS

As used in the specification and appended claims, unless specified tothe contrary, the following terms have the meaning indicated below.

“Amino” refers to the —NH2 radical.

“Cyano” refers to the —CN radical.

“Nitro” refers to the —NO2 radical.

“Oxa” refers to the —O— radical.

“Oxo” refers to the ═O radical.

“Thioxo” refers to the ═S radical.

“Imino” refers to the ═N—H radical.

“Oximo” refers to the ═N—OH radical.

“Hydrazino” refers to the ═N—NH2 radical.

“Alkyl” refers to a straight or branched hydrocarbon chain radicalconsisting solely of carbon and hydrogen atoms, containing nounsaturation, having from one to fifteen carbon atoms (e.g., C₁-C₁₅alkyl). In certain embodiments, an alkyl comprises one to thirteencarbon atoms (e.g., C₁-C₁₃ alkyl). In certain embodiments, an alkylcomprises one to eight carbon atoms (e.g., C₁-C₈ alkyl). In otherembodiments, an alkyl comprises one to five carbon atoms (e.g., C₁-C₅alkyl). In other embodiments, an alkyl comprises one to four carbonatoms (e.g., C₁-C₄ alkyl). In other embodiments, an alkyl comprises oneto three carbon atoms (e.g., C₁-C₃ alkyl). In other embodiments, analkyl comprises one to two carbon atoms (e.g., C₁-C₂ alkyl). In otherembodiments, an alkyl comprises one carbon atom (e.g., C₁ alkyl). Inother embodiments, an alkyl comprises five to fifteen carbon atoms(e.g., C₁-C₁₅ alkyl). In other embodiments, an alkyl comprises five toeight carbon atoms (e.g., C₅-C₈ alkyl). In other embodiments, an alkylcomprises two to five carbon atoms (e.g., C₂-C₅ alkyl). In otherembodiments, an alkyl comprises three to five carbon atoms (e.g., C₃-C₅alkyl). In other embodiments, the alkyl group is selected from methyl,ethyl, 1-propyl (n-propyl), 1-methylethyl (iso-propyl), 1-butyl(n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (iso-butyl),1,1-dimethylethyl (tert-butyl), 1-pentyl (n-pentyl). The alkyl isattached to the rest of the molecule by a single bond. Unless statedotherwise specifically in the specification, an alkyl group isoptionally substituted by one or more of the following substituents:halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl,—OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a))2, —C(O)R^(a), —C(O)OR^(a),—C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a), —OC(O)—N(R^(a))2,—N(R^(a))C(O)R^(a), —N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2),—S(O)_(t)OR^(a) (where t is 1 or 2), —S(O)_(t)R^(a) (where t is 1 or 2)and —S(O)_(t)N(R^(a))₂ (where t is 1 or 2) where each R^(a) isindependently hydrogen, alkyl (optionally substituted with halogen,hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl(optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), carbocyclylalkyl (optionally substituted with halogen,hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl),heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, ortrifluoro-methyl), heterocyclylalkyl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoro-methyl), heteroaryl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl), orheteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy,or trifluoromethyl).

“Alkoxy” refers to a radical bonded through an oxygen atom of theformula —O-alkyl, where alkyl is an alkyl chain as defined above.

“Alkenyl” refers to a straight or branched hydrocarbon chain radicalgroup consisting solely of carbon and hydrogen atoms, containing atleast one carbon-carbon double bond, and having from two to twelvecarbon atoms. In certain embodiments, an alkenyl comprises two to eightcarbon atoms. In other embodiments, an alkenyl comprises two to fourcarbon atoms. The alkenyl is attached to the rest of the molecule by asingle bond, for example, ethenyl (i.e., vinyl), prop-1-enyl (i.e.,allyl), but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like. Unlessstated otherwise specifically in the specification, an alkenyl group isoptionally substituted by one or more of the following substituents:halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl,—OR^(a), —SR^(a), OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a),—C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a), —OC(O)—N(R^(a))₂,—N(R^(a))C(O)R^(a), —N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2),—S(O)_(t)OR^(a) (where t is 1 or 2), —S(O)_(t)R^(a) (where t is 1 or 2)and —S(O)_(t)N(R^(a))₂ (where t is 1 or 2) where each R^(a) isindependently hydrogen, alkyl (optionally substituted with halogen,hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl(optionally substituted with halogen, hydroxy, methoxy, ortrifluoro-methyl), carbocyclylalkyl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoro-methyl), aryl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl(optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), heterocyclyl (optionally substituted with halogen,hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl),heteroaryl (optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), or heteroarylalkyl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl).

“Alkynyl” refers to a straight or branched hydrocarbon chain radicalgroup consisting solely of carbon and hydrogen atoms, containing atleast one carbon-carbon triple bond, having from two to twelve carbonatoms. In certain embodiments, an alkynyl comprises two to eight carbonatoms. In other embodiments, an alkynyl has two to four carbon atoms.The alkynyl is attached to the rest of the molecule by a single bond,for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and thelike. Unless stated otherwise specifically in the specification, analkynyl group is optionally substituted by one or more of the followingsubstituents: halo, cyano, nitro, oxo, thioxo, imino, oximo,trimethylsilanyl, —OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a))2,—C(O)R^(a), —C(O)OR^(a), —C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a),—OC(O)—N(R^(a))₂, —N(R^(a))C(O)R^(a), —N(R^(a))S(O)_(t)R^(a) (where t is1 or 2), —S(O)_(t)OR^(a) (where t is 1 or 2), —S(O)_(t)R^(a) (where t is1 or 2) and —S(O)_(t)N(R^(a))₂ (where t is 1 or 2) where each R^(a) isindependently hydrogen, alkyl (optionally substituted with halogen,hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl(optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), carbocyclylalkyl (optionally substituted with halogen,hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoro-methyl),heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), heterocyclylalkyl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl), orheteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy,or trifluoromethyl).

“Alkylene” or “alkylene chain” refers to a straight or branched divalenthydrocarbon chain linking the rest of the molecule to a radical group,consisting solely of carbon and hydrogen, containing no unsaturation andhaving from one to twelve carbon atoms, for example, methylene,ethylene, propylene, n-butylene, and the like. The alkylene chain isattached to the rest of the molecule through a single bond and to theradical group through a single bond. The points of attachment of thealkylene chain to the rest of the molecule and to the radical group canbe through one carbon in the alkylene chain or through any two carbonswithin the chain. In certain embodiments, an alkylene comprises one toeight carbon atoms (e.g., C₁-C₈ alkylene). In other embodiments, analkylene comprises one to five carbon atoms (e.g., C₁-C₅ alkylene). Inother embodiments, an alkylene comprises one to four carbon atoms (e.g.,C₁-C₄ alkylene). In other embodiments, an alkylene comprises one tothree carbon atoms (e.g., C₁-C₃ alkylene). In other embodiments, analkylene comprises one to two carbon atoms (e.g., C₁-C₂ alkylene). Inother embodiments, an alkylene comprises one carbon atom (e.g., C₁alkylene). In other embodiments, an alkylene comprises five to eightcarbon atoms (e.g., C₅-C₈ alkylene). In other embodiments, an alkylenecomprises two to five carbon atoms (e.g., C₂-C₅ alkylene). In otherembodiments, an alkylene comprises three to five carbon atoms (e.g.,C₃-C₅ alkylene). Unless stated otherwise specifically in thespecification, an alkylene chain is optionally substituted by one ormore of the following substituents: halo, cyano, nitro, oxo, thioxo,imino, oximo, trimethylsilanyl, —OR^(a), —SR^(a), OC(O)—R^(a),—N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a), —C(O)N(R^(a))₂,—N(R^(a))C(O)OR^(a), —OC(O)—N(R^(a))2, —N(R^(a))C(O)R^(a),—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)R^(a) (where t is 1 or 2) and —S(O)_(t)N(R^(a))₂(where t is 1 or 2) where each R^(a) is independently hydrogen, alkyl(optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl(optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), aryl (optionally substituted with halogen, hydroxy,methoxy, or trifluoromethyl), aralkyl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl),heterocyclylalkyl (optionally substituted with halogen, hydroxy,methoxy, or trifluoromethyl), heteroaryl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl(optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl).

“Alkynylene” or “alkynylene chain” refers to a straight or brancheddivalent hydrocarbon chain linking the rest of the molecule to a radicalgroup, consisting solely of carbon and hydrogen, containing at least onecarbon-carbon triple bond and having from two to twelve carbon atoms.The alkynylene chain is attached to the rest of the molecule through asingle bond and to the radical group through a single bond. In certainembodiments, an alkynylene comprises two to eight carbon atoms (e.g.,C₂-C₈ alkynylene). In other embodiments, an alkynylene comprises two tofive carbon atoms (e.g., C₂-C₅ alkynylene). In other embodiments, analkynylene comprises two to four carbon atoms (e.g., C₂-C₄ alkynylene).In other embodiments, an alkynylene comprises two to three carbon atoms(e.g., C₂-C₃ alkynylene). In other embodiments, an alkynylene comprisestwo carbon atoms (e.g., C₂ alkynylene). In other embodiments, analkynylene comprises five to eight carbon atoms (e.g., C₅-C₈alkynylene). In other embodiments, an alkynylene comprises two to fivecarbon atoms (e.g., C₂-C₅ alkynylene). In other embodiments, analkynylene comprises three to five carbon atoms (e.g., C₃-C₅alkynylene). Unless stated otherwise specifically in the specification,an alkynylene chain is optionally substituted by one or more of thefollowing substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo,trimethylsilanyl, —OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a))₂,—C(O)R^(a), —C(O)OR^(a), —C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a),—OC(O)—N(R^(a))₂, —N(R^(a))C(O)R^(a), —N(R^(a))S(O)_(t)R^(a) (where t is1 or 2), —S(O)_(t)OR^(a) (where t is 1 or 2), —S(O)_(t)R^(a) (where t is1 or 2) and —S(O)_(t)N(R^(a))₂ (where t is 1 or 2) where each R^(a) isindependently hydrogen, alkyl (optionally substituted with halogen,hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl(optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), carbocyclylalkyl (optionally substituted with halogen,hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl),heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), heterocyclylalkyl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl), orheteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy,or trifluoromethyl).

“Aryl” refers to a radical derived from an aromatic monocyclic ormulticyclic hydrocarbon ring system by removing a hydrogen atom from aring carbon atom. The aromatic monocyclic or multicyclic hydrocarbonring system contains only hydrogen and carbon from five to eighteencarbon atoms, where at least one of the rings in the ring system isfully unsaturated, i.e., it contains a cyclic, delocalized (4n+2)π-electron system in accordance with the Hückel theory. The ring systemfrom which aryl groups are derived include, but are not limited to,groups such as benzene, fluorene, indane, indene, tetralin andnaphthalene. Unless stated otherwise specifically in the specification,the term “aryl” or the prefix “ar-” (such as in “aralkyl”) is meant toinclude aryl radicals optionally substituted by one or more substituentsindependently selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl,cyano, nitro, optionally substituted aryl, optionally substitutedaralkyl, optionally substituted aralkenyl, optionally substitutedaralkynyl, optionally substituted carbocyclyl, optionally substitutedcarbocyclylalkyl, optionally substituted heterocyclyl, optionallysubstituted heterocyclylalkyl, optionally substituted heteroaryl,optionally substituted heteroarylalkyl, —R^(b)—OR^(a),—R^(b)—OC(O)—R^(a), —R^(b)—OC(O)—OR^(a), —R^(b)—OC(O)—N(R^(a))₂,—R^(b)—N(Ra)₂, —R^(b)—C(O)R^(a), —R^(b)—C(O)OR^(a), —R^(b)C(O)N(R^(a))₂,—R^(b)—O—R^(e)—C(O)N(Ra)₂, —R^(b)—N(R^(a))C(O)OR^(a),—R^(b)—N(R^(a))C(O)R^(a), —R^(b)—N(R^(a))S(O)_(t)R^(a) (where t is 1 or2), —R^(b)—S(O)_(t)R^(a) (where t is 1 or 2), —R^(b)—S(O)_(t)OR^(a)(where t is 1 or 2) and —R^(b)—S(O)_(t)N(R^(a))₂ (where t is 1 or 2),where each R^(a) is independently hydrogen, alkyl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl),fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy,methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substitutedwith halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl(optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), heterocyclyl (optionally substituted with halogen,hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl),heteroaryl (optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), or heteroarylalkyl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), each R^(b) isindependently a direct bond or a straight or branched alkylene oralkenylene chain, and R^(c) is a straight or branched alkylene oralkenylene chain, and where each of the above substituents isunsubstituted unless otherwise indicated.

“Aralkyl” refers to a radical of the formula —R^(e)-aryl where R^(c) isan alkylene chain as defined above, for example, methylene, ethylene,and the like. The alkylene chain part of the aralkyl radical isoptionally substtuted as described above for an alkylene chain. The arylpart of the aralkyl radical is optionally substituted as described abovefor an aryl group.

“Aralkenyl” refers to a radical of the formula —R^(d)-aryl where R^(d)is an alkenylene chain as defined above. The aryl part of the aralkenylradical is optionally substituted as described above for an aryl group.The alkenylene chain part of the aralkenyl radical is optionallysubstituted as defined above for an alkenylene group.

“Aralkynyl” refers to a radical of the formula —R^(e)-aryl, where R^(e)is an alkynylene chain as defined above. The aryl part of the aralkynylradical is optionally substituted as described above for an aryl group.The alkynylene chain part of the aralkynyl radical is optionallysubstituted as defined above for an alkynylene chain.

“Aralkoxy” refers to a radical bonded through an oxygen atom of theformula —O—R^(c)-aryl where R^(c) is an alkylene chain as defined above,for example, methylene, ethylene, and the like. The alkylene chain partof the aralkyl radical is optionally substituted as described above foran alkylene chain. The aryl part of the aralkyl radical is optionallysubstituted as described above for an aryl group.

“Carbocyclyl” refers to a stable non-aromatic monocyclic or polycyclichydrocarbon radical consisting solely of carbon and hydrogen atoms,which includes fused or bridged ring systems, having from three tofifteen carbon atoms. In certain embodiments, a carbocyclyl comprisesthree to ten carbon atoms. In other embodiments, a carbocyclyl comprisesfive to seven carbon atoms. The carbocyclyl is attached to the rest ofthe molecule by a single bond. Carbocyclyl may be saturated, (i.e.,containing single C—C bonds only) or unsaturated (i.e., containing oneor more double bonds or triple bonds). A fully saturated carbocyclylradical is also referred to as “cycloalkyl.” Examples of monocycliccycloalkyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, and cyclooctyl. An unsaturated carbocyclyl isalso referred to as “cycloalkenyl.” Examples of monocyclic cycloalkenylsinclude, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, andcyclooctenyl. Polycyclic carbocyclyl radicals include, for example,adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbornenyl,decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unlessotherwise stated specifically in the specification, the term“carbocyclyl” is meant to include carbocyclyl radicals that areoptionally substituted by one or more substituents independentlyselected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo,cyano, nitro, optionally substituted aryl, optionally substitutedaralkyl, optionally substituted aralkenyl, optionally substitutedaralkynyl, optionally substituted carbocyclyl, optionally substitutedcarbocyclylalkyl, optionally substituted heterocyclyl, optionallysubstituted heterocyclylalkyl, optionally substituted heteroaryl,optionally substituted heteroarylalkyl, —R^(b)—OR^(a),—R^(b)—OC(O)—R^(a), —R^(b)—OC(O)—OR^(a), —R^(b)—OC(O)—N(R^(a))₂,—R^(b)—N(Ra)₂, —R^(b)—C(O)R^(a), —R^(b)—C(O)OR^(a), —R^(b)C(O)N(R^(a))₂,—R^(b)—O—R^(c)—C(O)N(R^(a))₂, —R^(b)—N(R^(a))C(O)OR^(a),—R^(b)—N(R^(a))C(O)R^(a), —R^(b)—N(R^(a))S(O)_(t)R^(a) (where t is 1 or2), —R^(b)—S(O)_(t)R^(a) (where t is 1 or 2), —R^(b)—S(O)_(t)OR^(a)(where t is 1 or 2) and —R^(b)—S(O)_(t)N(R^(a))₂ (where t is 1 or 2),where each R^(a) is independently hydrogen, alkyl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl),fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy,methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substitutedwith halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl(optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), heterocyclyl (optionally substituted with halogen,hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl),heteroaryl (optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), or heteroarylalkyl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), each R^(b) isindependently a direct bond or a straight or branched alkylene oralkenylene chain, and R^(c) is a straight or branched alkylene oralkenylene chain, and where each of the above substituents isunsubstituted unless otherwise indicated.

“Carbocyclylalkyl” refers to a radical of the formula —R^(c)-carbocyclylwhere R^(c) is an alkylene chain as defined above. The alkylene chainand the carbocyclyl radical is optionally substituted as defined above.

“Carbocyclylalkoxy” refers to a radical bonded through an oxygen atom ofthe formula —O—R^(c)-carbocyclyl where R^(c) is an alkylene chain asdefined above. The alkylene chain and the carbocyclyl radical isoptionally substituted as defined above.

“Carbocyclylalkynyl” refers to a radical of the formula—R^(c)-carbocyclyl, where R^(c) is an alkynylene chain as defined above.The carbocyclyl part of the carbocyclylalkynyl radical is optionallysubstituted as described above for an carbocyclyl group. In someembodiments the carbocyclyl group is a cycloalkyl group. The alkynylenechain part of the carbocyclylalkynyl radical is optionally substitutedas defined above for an alkynylene chain.

As used herein, “carboxylic acid bioisostere” refers to a functionalgroup or moiety that exhibits similar physical, biological and/orchemical properties as a carboxylic acid moiety. Examples of carboxylicacid bioisosteres include, but are not limited to,

and the like.

“Halo” or “halogen” refers to bromo, chloro, fluoro or iodosubstituents.

“Fluoroalkyl” refers to an alkyl radical, as defined above, that issubstituted by one or more fluoro radicals, as defined above, forexample, trifluoromethyl, difluoromethyl, fluoromethyl,2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like. Thealkyl part of the fluoroalkyl radical may be optionally substituted asdefined above for an alkyl group.

“Heterocyclyl” refers to a stable 3- to 18-membered non-aromatic ringradical that comprises two to twelve carbon atoms and from one to sixheteroatoms selected from nitrogen, oxygen and sulfur. Unless statedotherwise specifically in the specification, the heterocyclyl radical isa monocyclic, bicyclic, tricyclic or tetracyclic ring system, which mayinclude fused or bridged ring systems. The heteroatoms in theheterocyclyl radical may be optionally oxidized. One or more nitrogenatoms, if present, are optionally quaternized. The heterocyclyl radicalis partially or fully saturated. The heterocyclyl may be attached to therest of the molecule through any atom of the ring(s). Examples of suchheterocyclyl radicals include, but are not limited to, dioxolanyl,thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl,imidazolidinyl, isothiazolidinyl, iso-xazolidinyl, morpholinyl,octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl,2-oxo-piperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl,piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl,thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl,thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in thespecification, the term “heterocyclyl” is meant to include heterocyclylradicals as defined above that are optionally substituted by one or moresubstituents selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl,oxo, thioxo, cyano, nitro, optionally substituted aryl, optionallysubstituted aralkyl, optionally substituted aralkenyl, optionallysubstituted aralkynyl, optionally substituted carbocyclyl, optionallysubstituted carbocyclylalkyl, optionally substituted heterocyclyl,optionally substituted heterocyclylalkyl, optionally substitutedheteroaryl, optionally substituted heteroarylalkyl, —R^(b)—OR^(a),—R^(b)—OC(O)—R^(a), —R^(b)—OC(O)—OR^(a), —R^(b)—OC(O)—N(R^(a))₂,—R^(b)—N(Ra)₂, —R^(b)—C(O)R^(a), —R^(b)—C(O)OR^(a), —R^(b)C(O)N(R^(a))₂,—R^(b)—O—R^(c)—C(O)N(R^(a))₂, —R^(b)—N(R^(a))C(O)OR^(a),—R^(b)—N(R^(a))C(O)R^(a), —R^(b)—N(R^(a))S(O)_(t)R^(a) (where t is 1 or2), —R^(b)—S(O)_(t)R^(a) (where t is 1 or 2), —R^(b)—S(O)_(t)OR^(a)(where t is 1 or 2) and —R^(b)—S(O)_(t)N(R^(a))₂ (where t is 1 or 2),where each R^(a) is independently hydrogen, alkyl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl),fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy,methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substitutedwith halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl(optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), heterocyclyl (optionally substituted with halogen,hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl),heteroaryl (optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), or heteroarylalkyl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), each R^(b) isindependently a direct bond or a straight or branched alkylene oralkenylene chain, and R^(c) is a straight or branched alkylene oralkenylene chain, and where each of the above substituents isunsubstituted unless otherwise indicated.

“N-heterocyclyl” or “N-attached heterocyclyl” refers to a heterocyclylradical as defined above containing at least one nitrogen and where thepoint of attachment of the heterocyclyl radical to the rest of themolecule is through a nitrogen atom in the heterocyclyl radical. AnN-heterocyclyl radical is optionally substituted as described above forheterocyclyl radicals. Examples of such N-heterocyclyl radicals include,but are not limited to, 1-morpholinyl, 1-piperidinyl, 1-piperazinyl,1-pyrrolidinyl, pyrazolidinyl, imidazolinyl, and imidazolidinyl.

“C-heterocyclyl” or “C-attached heterocyclyl” refers to a heterocyclylradical as defined above containing at least one heteroatom and wherethe point of attachment of the heterocyclyl radical to the rest of themolecule is through a carbon atom in the heterocyclyl radical. AC-heterocyclyl radical is optionally substituted as described above forheterocyclyl radicals. Examples of such C-heterocyclyl radicals include,but are not limited to, 2-morpholinyl, 2- or 3- or 4-piperidinyl,2-piperazinyl, 2- or 3-pyrrolidinyl, and the like.

“Heterocyclylalkyl” refers to a radical of the formula—R^(c)-heterocyclyl where R^(c) is an alkylene chain as defined above.If the heterocyclyl is a nitrogen-containing heterocyclyl, theheterocyclyl is optionally attached to the alkyl radical at the nitrogenatom. The alkylene chain of the heterocyclylalkyl radical is optionallysubstituted as defined above for an alkylene chain. The heterocyclylpart of the heterocyclylalkyl radical is optionally substituted asdefined above for a heterocyclyl group.

“Heterocyclylalkoxy” refers to a radical bonded through an oxygen atomof the formula —O-Rc-heterocyclyl where R^(c) is an alkylene chain asdefined above. If the heterocyclyl is a nitrogen-containingheterocyclyl, the heterocyclyl is optionally attached to the alkylradical at the nitrogen atom. The alkylene chain of theheterocyclylalkoxy radical is optionally substituted as defined abovefor an alkylene chain. The heterocyclyl part of the heterocyclylalkoxyradical is optionally substituted as defined above for a heterocyclylgroup.

“Heteroaryl” refers to a radical derived from a 3- to 18-memberedaromatic ring radical that comprises two to seventeen carbon atoms andfrom one to six heteroatoms selected from nitrogen, oxygen and sulfur.As used herein, the heteroaryl radical may be a monocyclic, bicyclic,tricyclic or tetracyclic ring system, wherein at least one of the ringsin the ring system is fully unsaturated, i.e., it contains a cyclic,delocalized (4n+2) π-electron system in accordance with the Hückeltheory. Heteroaryl includes fused or bridged ring systems. Theheteroatom(s) in the heteroaryl radical is optionally oxidized. One ormore nitrogen atoms, if present, are optionally quaternized. Theheteroaryl is attached to the rest of the molecule through any atom ofthe ring(s). Examples of heteroaryls include, but are not limited to,azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl,benzofuranyl, benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl,benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl,benzonaphthofuranyl, benz-oxazolyl, benzodioxolyl, benzodioxinyl,benzopyranyl, benzopyranonyl, benzofuranyl, benzo-furanonyl,benzothienyl (benzothiophenyl), benzothieno[3,2-d]pyrimidinyl,benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl,cinnolinyl, cyclopenta[d]pyrimidinyl,6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl,5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl,6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl,dibenzothiophenyl, furanyl, furanonyl, furo[3,2-c]pyridinyl,5,6,7,8,9,10-hexahydrocycloocta[d]-pyrimidinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl,5,6,7,8,9,10-hexahydrocycloocta[d]-pyridinyl, isothiazolyl, imidazolyl,indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl,isoquinolyl, indolizinyl, isoxazolyl,5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl,1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl,5,6,6a,7,8,9,10,10a-octa-hydrobenzo[h]quinazolinyl,1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl,phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl,pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl,pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl,quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl,tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl,5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl,6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl,5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thia-diazolyl,triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl,thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pridinyl, and thiophenyl (i.e.thienyl). Unless stated otherwise specifically in the specification, theterm “heteroaryl” is meant to include heteroaryl radicals as definedabove which are optionally substituted by one or more substituentsselected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, haloalkenyl,haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl,optionally substituted aralkyl, optionally substituted aralkenyl,optionally substituted aralkynyl, optionally substituted carbocyclyl,optionally substituted carbocyclylalkyl, optionally substitutedheterocyclyl, optionally substituted heterocyclylalkyl, optionallysubstituted heteroaryl, optionally substituted heteroarylalkyl,—R^(b)—OR^(a), —R^(b)—OC(O)—R^(a), —R^(b)—OC(O)—OR^(a),—R^(b)—OC(O)—N(R^(a))₂, —R^(b)—N(Ra)₂, —R^(b)—C(O)Ra, —R^(b)—C(O)OR^(a),—R^(b)C(O)N(R^(a))₂, —R^(b)—O—R^(c)—C(O)N(R^(a))₂,—R^(b)—N(R^(a))C(O)OR^(a), —R^(b)—N(R^(a))C(O)R^(a),—R^(b)—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —R^(b)—S(O)_(t)R^(a)(where t is 1 or 2), —R^(b)—S(O)_(t)OR^(a) (where t is 1 or 2) and—R^(b)—S(O)_(t)N(R^(a))₂ (where t is 1 or 2), where each R^(a) isindependently hydrogen, alkyl (optionally substituted with halogen,hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl(optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), cycloalkylalkyl (optionally substituted with halogen,hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl),heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), heterocyclylalkyl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl), orheteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy,or trifluoromethyl), each R^(b) is independently a direct bond or astraight or branched alkylene or alkenylene chain, and R^(c) is astraight or branched alkylene or alkenylene chain, and where each of theabove substituents is unsubstituted unless otherwise indicated.

“N-heteroaryl” refers to a heteroaryl radical as defined abovecontaining at least one nitrogen and where the point of attachment ofthe heteroaryl radical to the rest of the molecule is through a nitrogenatom in the heteroaryl radical. An N-heteroaryl radical is optionallysubstituted as described above for heteroaryl radicals.

“C-heteroaryl” refers to a heteroaryl radical as defined above and wherethe point of attachment of the heteroaryl radical to the rest of themolecule is through a carbon atom in the heteroaryl radical. AC-heteroaryl radical is optionally substituted as described above forheteroaryl radicals.

“Heteroarylalkyl” refers to a radical of the formula —R^(c)-heteroaryl,where R^(c) is an alkylene chain as defined above. If the heteroaryl isa nitrogen-containing heteroaryl, the heteroaryl is optionally attachedto the alkyl radical at the nitrogen atom. The alkylene chain of theheteroarylalkyl radical is optionally substituted as defined above foran alkylene chain. The heteroaryl part of the heteroarylalkyl radical isoptionally substituted as defined above for a heteroaryl group.

“Heteroarylalkoxy” refers to a radical bonded through an oxygen atom ofthe formula —O—R^(c)-heteroaryl, where R^(c) is an alkylene chain asdefined above. If the heteroaryl is a nitrogen-containing heteroaryl,the heteroaryl is optionally attached to the alkyl radical at thenitrogen atom. The alkylene chain of the heteroarylalkoxy radical isoptionally substituted as defined above for an alkylene chain. Theheteroaryl part of the heteroarylalkoxy radical is optionallysubstituted as defined above for a heteroaryl group.

The compounds disclosed herein may contain one or more asymmetriccenters and may thus give rise to enantiomers, diastereomers, and otherstereoisomeric forms that may be defined, in terms of absolutestereochemistry, as (R)- or (S)-. Unless stated otherwise, it isintended that all stereoisomeric forms of the compounds disclosed hereinare contemplated by this disclosure. When the compounds described hereincontain alkene double bonds, and unless specified otherwise, it isintended that this disclosure includes both E and Z geometric isomers(e.g., cis or trans) Likewise, all possible isomers, as well as theirracemic and optically pure forms, and all tautomeric forms are alsointended to be included. The term “geometric isomer” refers to E or Zgeometric isomers (e.g., cis or trans) of an alkene double bond. Theterm “positional isomer” refers to structural isomers around a centralring, such as ortho-, meta-, and para-isomers around a benzene ring.

A “tautomer” refers to a molecule wherein a proton shift from one atomof a molecule to another atom of the same molecule is possible. Thecompounds presented herein may, in certain embodiments, exist astautomers. In circumstances where tautomerization is possible, achemical equilibrium of the tautomers will exist. The exact ratio of thetautomers depends on several factors, including physical state,temperature, solvent, and pH. Some examples of tautomeric equilibriuminclude:

“Optional” or “optionally” means that a subsequently described event orcircumstance may or may not occur and that the description includesinstances when the event or circumstance occurs and instances in whichit does not. For example, “optionally substituted aryl” means that thearyl radical may or may not be substituted and that the descriptionincludes both substituted aryl radicals and aryl radicals having nosubstitution.

“Pharmaceutically acceptable salt” includes both acid and base additionsalts. A pharmaceutically acceptable salt of any one of the substitutedheterocyclic derivative compounds described herein is intended toencompass any and all pharmaceutically suitable salt forms. Preferredpharmaceutically acceptable salts of the compounds described herein arepharmaceutically acceptable acid addition salts and pharmaceuticallyacceptable base addition salts.

“Pharmaceutically acceptable acid addition salt” refers to those saltswhich retain the biological effectiveness and properties of the freebases, which are not biologically or otherwise undesirable, and whichare formed with inorganic acids such as hydrochloric acid, hydrobromicacid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid,hydrofluoric acid, phosphorous acid, and the like. Also included aresalts that are formed with organic acids such as aliphatic mono- anddicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoicacids, alkanedioic acids, aromatic acids, aliphatic and aromaticsulfonic acids, etc., and include, for example, acetic acid,trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid,oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid,tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid,salicylic acid, and the like. Exemplary salts thus include sulfates,pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates,monohydrogenphosphates, dihydrogenphosphates, metaphosphates,pyrophosphates, chlorides, bromides, iodides, acetates,trifluoroacetates, propionates, caprylates, isobutyrates, oxalates,malonates, succinate suberates, sebacates, fumarates, maleates,mandelates, benzoates, chlorobenzoates, methylbenzoates,dinitrobenzoates, phthalates, benzenesulfonates, toluene-sulfonates,phenylacetates, citrates, lactates, malates, tartrates,methanesulfonates, and the like. Also contemplated are salts of aminoacids, such as arginates, gluconates, and galacturonates (see, e.g.,Berge S M et al., Pharmaceutical Salts, J. Pharm. Sci. 66:1-19 (1997)).Acid addition salts of basic compounds may be prepared by contacting thefree base forms with a sufficient amount of the desired acid to producethe salt according to methods and techniques with which a skilledartisan is familiar.

“Pharmaceutically acceptable base addition salt” refers to those saltsthat retain the biological effectiveness and properties of the freeacids, which are not biologically or otherwise undesirable. These saltsare prepared from addition of an inorganic base or an organic base tothe free acid. Pharmaceutically acceptable base addition salts may beformed with metals or amines, such as alkali and alkaline earth metalsor organic amines. Salts derived from inorganic bases include, but arenot limited to, sodium, potassium, lithium, ammonium, calcium,magnesium, iron, zinc, copper, manganese, aluminum salts and the like.Salts derived from organic bases include, but are not limited to, saltsof primary, secondary, and tertiary amines, substituted amines includingnaturally occurring substituted amines, cyclic amines and basic ionexchange resins, for example, isopropylamine, trimethylamine,diethylamine, triethylamine, tripropylamine, ethanolamine,diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol,dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine,N,N-dibenzylethylenediamine, chloroprocaine, hydrabamine, choline,betaine, ethylenediamine, ethylenedianiline, N-methylglucamine,glucosamine, methylglucamine, theobromine, purines, piperazine,piperidine, N-ethylpiperidine, polyamine resins and the like. See Bergeet al., supra.

As used herein, “treatment” or “treating,” or “palliating” or“ameliorating” are used interchangeably herein. These terms refers to anapproach for obtaining beneficial or desired results including but notlimited to therapeutic benefit and/or a prophylactic benefit. By“therapeutic benefit” is meant eradication or amelioration of theunderlying disorder being treated. Also, a therapeutic benefit isachieved with the eradication or amelioration of one or more of thephysiological symptoms associated with the underlying disorder such thatan improvement is observed in the patient, notwithstanding that thepatient may still be afflicted with the underlying disorder. Forprophylactic benefit, the compositions may be administered to a patientat risk of developing a particular disease, or to a patient reportingone or more of the physiological symptoms of a disease, even though adiagnosis of this disease may not have been made.

“Prodrug” is meant to indicate a compound that may be converted underphysiological conditions or by solvolysis to a biologically activecompound described herein. Thus, the term “prodrug” refers to aprecursor of a biologically active compound that is pharmaceuticallyacceptable. A prodrug may be inactive when administered to a subject,but is converted in vivo to an active compound, for example, byhydrolysis. The prodrug compound often offers advantages of solubility,tissue compatibility or delayed release in a mammalian organism (see,e.g., Bundgard, H, DESIGN OF PRODRUGS (1985) pp. 7-9, 21-24 (Elsevier,Amsterdam).

A discussion of prodrugs is provided in Higuchi, T, et al., “Pro-drugsas Novel Delivery Systems,” A.C.S. Symposium Series, Vol. 14, and inBIOREVERSIBLE CARRIERS IN DRUG DESIGN, ed. Edward B. Roche, AmericanPharmaceutical Association and Pergamon Press, 1987. The term “prodrug”is also meant to include any covalently bonded carriers, which releasethe active compound in vivo when such prodrug is administered to amammalian subject. Prodrugs of an active compound, as described herein,may be prepared by modifying functional groups present in the activecompound in such a way that the modifications are cleaved, either inroutine manipulation or in vivo, to the parent active compound. Prodrugsinclude compounds wherein a hydroxy, amino or mercapto group is bondedto any group that, when the prodrug of the active compound isadministered to a mammalian subject, cleaves to form a free hydroxy,free amino or free mercapto group, respectively. Examples of prodrugsinclude, but are not limited to, acetate, formate and benzoatederivatives of alcohol or amine functional groups in the activecompounds and the like.

Unless otherwise stated, structures depicted herein are intended toinclude compounds which differ only in the presence of one or moreisotopically enriched atoms. For example, compounds having the presentstructures except for the replacement of a hydrogen by a deuterium ortritium, or the replacement of a carbon by ¹³C- or ¹⁴C-enriched carbonare within the scope of the present disclosure.

The compounds of the present disclosure optionally contain unnaturalproportions of atomic isotopes at one or more atoms that constitute suchcompounds. For example, the compounds may be labeled with isotopes, suchas for example, deuterium (²H), tritium (³H), iodine-125 (¹²⁵I) orcarbon-14 (¹⁴C). Isotopic substitution with ²H, ¹¹C, ¹³C, ¹⁴C, ¹⁵C, ¹²N,¹³N, ¹⁵N, ¹⁶N, ¹⁶O, ¹⁷O, ¹⁴F, ¹⁵F, ¹⁶F, ¹⁷F, ¹⁸F, ³³S, ³⁴S, ³⁵S, ³⁶S,³⁵Cl, ³⁷Cl, ⁷⁹Br, ⁸¹Br, ¹²⁵I are all contemplated. All isotopicvariations of the compounds of the present invention, whetherradioactive or not, are encompassed within the scope of the presentinvention.

In certain embodiments, the compounds disclosed herein have some or allof the ¹H atoms replaced with ²H atoms. The methods of synthesis fordeuterium-containing substituted heterocyclic derivative compounds areknown in the art and include, by way of non-limiting example only, thefollowing synthetic methods.

Deuterated starting materials are readily available and are subjected tothe synthetic methods described herein to provide for the synthesis ofdeuterium-containing substituted heterocyclic derivative compounds.Large numbers of deuterium-containing reagents and building blocks areavailable commerically from chemical vendors, such as Aldrich ChemicalCo.

Deuterium-transfer reagents suitable for use in nucleophilicsubstitution reactions, such as iodomethane-d₃ (CD₃I), are readilyavailable and may be employed to transfer a deuterium-substituted carbonatom under nucleophilic substitution reaction conditions to the reactionsubstrate. The use of CD₃I is illustrated, by way of example only, inthe reaction schemes below.

Deuterium-transfer reagents, such as lithium aluminum deuteride(LiAlD₄), are employed to transfer deuterium under reducing conditionsto the reaction substrate. The use of LiAlD₄ is illustrated, by way ofexample only, in the reaction schemes below.

Deuterium gas and palladium catalyst are employed to reduce unsaturatedcarbon-carbon linkages and to perform a reductive substitution of arylcarbon-halogen bonds as illustrated, by way of example only, in thereaction schemes below.

In one embodiment, the compounds disclosed herein contain one deuteriumatom. In another embodiment, the compounds disclosed herein contain twodeuterium atoms. In another embodiment, the compounds disclosed hereincontain three deuterium atoms. In another embodiment, the compoundsdisclosed herein contain four deuterium atoms. In another embodiment,the compounds disclosed herein contain five deuterium atoms. In anotherembodiment, the compounds disclosed herein contain six deuterium atoms.In another embodiment, the compounds disclosed herein contain more thansix deuterium atoms. In another embodiment, the compound disclosedherein is fully substituted with deuterium atoms and contains nonon-exchangeable ¹H hydrogen atoms. In one embodiment, the level ofdeuterium incorporation is determined by synthetic methods in which adeuterated synthetic building block is used as a starting material.

Substituted Heterocyclic Derivative Compounds

Substituted heterocyclic derivative compounds are described herein thatare bromodomain inhibitors. These compounds, and compositions comprisingthese compounds, are useful for the treatment of cancer and neoplasticdisease. The compounds described herein may, therefore, be useful fortreating NUT midline carcinoma, Burkitts lymphoma, prostate cancer,breast cancer, bladder cancer, lung cancer and/or melanoma and the like.

One embodiment provides a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof,

wherein,

-   -   R² is selected from CH₃, CH₂CH₃, CH₂CF₃, CH₂F, CHF₂, CF₃, CH₂D,        CHD₂, or CD₃;    -   X5 is C—R⁵ or N;    -   X6 is C—R⁶ or N;    -   X7 is C—R⁷ or N;    -   X8 is C—R⁸ or N; wherein no more than two of X5, X6, X7, or X8        may be N;        -   R⁵ is hydrogen, halogen, —OH, —CN, —OR⁶¹, —NHR⁶¹, —N(R⁶¹)₂,            alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl,            heterocyclyl, heterocyclylalkyl, heteroaryl, or            heteroarylalkyl, wherein each R⁶¹ is independently selected            from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl,            heterocyclyl, heterocyclylalkyl, heteroaryl, or            heteroarylalkyl;        -   R⁶ is hydrogen, halogen, —OH, —CN, —OR⁶¹, —NHR⁶¹, —N(R⁶¹)₂,            alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl,            heterocyclyl, heterocyclylalkyl, heteroaryl, or            heteroarylalkyl, wherein each R⁶¹ is independently selected            from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl,            heterocyclyl, heterocyclylalkyl, heteroaryl, or            heteroarylalkyl;        -   R⁷ is hydrogen, halogen, —OH, —CN, —OR⁶¹, —NHR⁶¹, —N(R⁶¹)₂,            alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl,            heterocyclyl, heterocyclylalkyl, heteroaryl, or            heteroarylalkyl, wherein each R⁶¹ is independently selected            from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl,            heterocyclyl, heterocyclylalkyl, heteroaryl, or            heteroarylalkyl;        -   R⁸ is hydrogen, halogen, or alkyl;    -   R^(A) is

-   -   -   X2 is N or C—R¹², wherein R¹² is hydrogen, halogen, alkyl,            or alkoxy;        -   R¹³ is —Y—Z;        -   Y is selected from a bond, —CH₂—, —CH(C₁-C₄ alkyl)-;        -   Z is selected from —SO₂R²¹, —N(R²²)SO₂R²¹, —SO₂N(R²²)₂,            —N(R²²)SO₂N(R²²)₂, —CON(R²²)₂, —N(R²²)CO₂R²¹,            —N(R²²)CON(R²²)₂, —N(R²²)COR²¹, —COR²¹, —OC(O)N(R²²)₂,            —OSO₂N(R²²)₂, or —N(R²²)SO₃R²¹;        -   X3 is N or C—R¹⁴, wherein R¹⁴ is hydrogen, halogen, —CN,            alkyl, cycloalkyl, or alkoxy;        -   X4 is N or C—R¹⁵, wherein R¹⁵ is hydrogen, halogen, alkyl,            —CN, or alkoxy;        -   R¹⁶ is hydrogen, halogen, or —W—X, wherein W is a bond, —O—,            —S—, or —NH—, and X is selected from alkyl, aryl, aralkyl,            cycloalkyl, cycloalkylalkyl, alkynyl, cycloalkylalkynyl,            heterocyclyl, heterocyclylalkyl, heteroaryl, or            heteroarylalkyl; each R²¹ is independently selected from            alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl,            heterocyclyl, heterocyclylalkyl, heteroaryl, or            heteroarylalkyl; and each R²² is independently selected from            hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl,            heterocyclyl, heterocyclylalkyl, heteroaryl, or            heteroarylalkyl.

Another embodiment provides a compound of Formula (I), wherein R² isCH₃. Another embodiment provides a compound of Formula (I), wherein R²is CD₃. Another embodiment provides a compound of Formula (I), whereinX5 is N. Another embodiment provides a compound of Formula (I), whereinX6 is N. Another embodiment provides a compound of Formula (I), whereinX7 is N. Another embodiment provides a compound of Formula (I), whereinX8 is N. Another embodiment provides a compound of Formula (I), whereinnone of X5, X6, X7, or X8 is N. Another embodiment provides a compoundof Formula (I), wherein R⁵ and R⁸ are hydrogen. Another embodimentprovides a compound of Formula (I), wherein R⁵, R⁶, R⁷ and R⁸ arehydrogen. Another embodiment provides a compound of Formula (I), whereinR⁷ is a halogen. Another embodiment provides a compound of Formula (I),wherein R⁶ is a halogen. Another embodiment provides a compound ofFormula (I), wherein R⁶ is a heteroaryl. Another embodiment provides acompound of Formula (I), wherein R⁶ is an aryl. Another embodimentprovides a compound of Formula (I), wherein R⁶ is an alkyl. Anotherembodiment provides a compound of Formula (I), wherein R⁶ is an aryl.

Another embodiment provides a compound of Formula (I), wherein Y is abond. Another embodiment provides a compound of Formula (I), wherein Yis a —CH₂—. Another embodiment provides a compound of Formula (I),wherein Z is —SO₂R²¹. Another embodiment provides a compound of Formula(I), wherein Z is —N(R²²)SO₂R²¹. Another embodiment provides a compoundof Formula (I), wherein Z is —SO₂N(R²²)₂. Another embodiment provides acompound of Formula (I), wherein Z is —N(R²²)SO₂N(R²²)₂. Anotherembodiment provides a compound of Formula (I), wherein Z is —CON(R²²)₂.Another embodiment provides a compound of Formula (I), wherein Z is—N(R²²)CO₂R²¹. Another embodiment provides a compound of Formula (I),wherein Z is —N(R²²)CON(R²²)₂. Another embodiment provides a compound ofFormula (I), wherein R21 is alkyl, cycloalkyl, or cycloalkylalkyl.Another embodiment provides a compound of Formula (I), wherein R²¹ isalkyl. Another embodiment provides a compound of Formula (I), whereinR¹⁴ is hydrogen, halogen, or alkyl. Another embodiment provides acompound of Formula (I), wherein X4 is C—R¹⁵. Another embodimentprovides a compound of Formula (I), wherein W is —O—. Another embodimentprovides a compound of Formula (I), wherein W is —NH—. Anotherembodiment provides a compound of Formula (I), wherein X is alkyl.Another embodiment provides a compound of Formula (I), wherein X isaryl. Another embodiment provides a compound of Formula (I), wherein Xis cycloalkylalkyl. Another embodiment provides a compound of Formula(I), wherein W is —O— and X is alkyl. Another embodiment provides acompound of Formula (I), wherein W is —O— and X is aryl. Anotherembodiment provides a compound of Formula (I), wherein W is —O— and X iscycloalkylalkyl. Another embodiment provides a compound of Formula (I),wherein R⁵ and R⁸ are hydrogen. Another embodiment provides a compoundof Formula (I), wherein R⁵ and R⁸ are hydrogen, and R⁶ is heteroaryl.

One embodiment provides a compound of Formula (Ia), or apharmaceutically acceptable salt thereof,

-   -   wherein,    -   R² is selected from CH₃, CH₂CH₃, CH₂CF₃, CH₂F, CHF₂, CF₃, CH₂D,        CHD₂, or CD₃;    -   X5 is C—R⁵ or N;    -   X6 is C—R⁶ or N;    -   X7 is C—R⁷ or N;    -   X8 is C—R⁸ or N; wherein no more than two of X5, X6, X7, or X8        may be N;    -   R⁵ is hydrogen, halogen, —OH, —CN, —OR⁶¹, —NHR⁶¹, —N(R⁶¹)₂,        alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,        heterocyclylalkyl, heteroaryl, or heteroarylalkyl, wherein each        R⁶¹ is independently selected from alkyl, cycloalkyl,        cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,        heteroaryl, or heteroarylalkyl;    -   R⁶ is hydrogen, halogen, —OH, —CN, —OR⁶¹, —NHR⁶¹, —N(R⁶¹)₂,        alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,        heterocyclylalkyl, heteroaryl, or heteroarylalkyl, wherein each        R⁶¹ is independently selected from alkyl, cycloalkyl,        cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,        heteroaryl, or heteroarylalkyl;    -   R⁷ is hydrogen, halogen, —OH, —CN, —OR⁶¹, —NHR⁶¹, —N(R⁶¹)₂,        alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,        heterocyclylalkyl, heteroaryl, or heteroarylalkyl, wherein each        R⁶¹ is independently selected from alkyl, cycloalkyl,        cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,        heteroaryl, or heteroarylalkyl;    -   R⁸ is hydrogen, halogen, or alkyl;    -   R^(A) is

-   -   X2 is N or C—R¹², wherein R¹² is hydrogen, halogen, alkyl, or        alkoxy;    -   R¹³ is —Y—Z;    -   Y is selected from a bond, or —CH₂—;    -   Z is selected from —SO₂R²¹, —N(R²²)SO₂R²¹, —SO₂N(R²²)₂,        —N(R²²)SO₂N(R²²)₂, —CON(R²²)₂, —N(R²²)CO₂R²¹, —N(R²²)CON(R²²)₂,        —N(R²²)COR²¹, —OC(O)N(R²²)₂, —OSO₂N(R²²)₂, or —N(R²²)SO₃R²¹;    -   X3 is N or C—R¹⁴, wherein R¹⁴ is hydrogen, halogen, —CN, alkyl,        cycloalkyl, or alkoxy;    -   X4 is N or C—R¹⁵, wherein R¹⁵ is hydrogen, halogen, alkyl, —CN,        or alkoxy;    -   R¹⁶ is hydrogen, halogen, or —W—X, wherein W is a bond, —O—,        —S—, or —NH—, and X is selected from alkyl, aryl, aralkyl,        cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl,        heteroaryl, or heteroarylalkyl;    -   each R²¹ is independently selected from alkyl, cycloalkyl,        cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,        heteroaryl, or heteroarylalkyl; and    -   each R²² is independently selected from hydrogen, alkyl,        cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,        heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

Another embodiment provides a compound of Formula (Ia), wherein R² isCH₃. Another embodiment provides a compound of Formula (Ia), wherein R²is CD₃. Another embodiment provides a compound of Formula (Ia), whereinX5 is N. Another embodiment provides a compound of Formula (Ia), whereinX6 is N. Another embodiment provides a compound of Formula (Ia), whereinX7 is N. Another embodiment provides a compound of Formula (Ia), whereinX8 is N. Another embodiment provides a compound of Formula (Ia), whereinnone of X5, X6, X7, or X8 is N. Another embodiment provides a compoundof Formula (Ia), wherein R⁵ and R⁸ are hydrogen. Another embodimentprovides a compound of Formula (Ia), wherein R⁵, R⁶, R⁷ and R⁸ arehydrogen. Another embodiment provides a compound of Formula (Ia),wherein R⁷ is a halogen. Another embodiment provides a compound ofFormula (Ia), wherein R⁶ is a halogen. Another embodiment provides acompound of Formula (Ia), wherein R⁶ is a heteroaryl. Another embodimentprovides a compound of Formula (Ia), wherein R⁶ is an aryl. Anotherembodiment provides a compound of Formula (Ia), wherein R⁶ is an alkyl.Another embodiment provides a compound of Formula (Ia), wherein R⁶ is anaryl.

Another embodiment provides a compound of Formula (Ia), wherein Y is abond. Another embodiment provides a compound of Formula (Ia), wherein Yis a —CH₂—. Another embodiment provides a compound of Formula (Ia),wherein Z is —SO2R²¹. Another embodiment provides a compound of Formula(Ia), wherein Z is —N(R²²)SO₂R²¹. Another embodiment provides a compoundof Formula (Ia), wherein Z is —SO₂N(R²²)₂. Another embodiment provides acompound of Formula (Ia), wherein Z is —N(R²²)SO₂N(R²²)₂. Anotherembodiment provides a compound of Formula (Ia), wherein Z is —CON(R²²)₂.Another embodiment provides a compound of Formula (Ia), wherein Z is—N(R²²)CO₂R²¹. Another embodiment provides a compound of Formula (Ia),wherein Z is —N(R²²)CON(R²²)₂. Another embodiment provides a compound ofFormula (Ia), wherein R²¹ is alkyl, cycloalkyl, or cycloalkylalkyl.Another embodiment provides a compound of Formula (Ia), wherein R²¹ isalkyl. Another embodiment provides a compound of Formula (Ia), whereinR¹⁴ is hydrogen, halogen, or alkyl. Another embodiment provides acompound of Formula (Ia), wherein X4 is C—R¹⁵. Another embodimentprovides a compound of Formula (Ia), wherein W is —O—. Anotherembodiment provides a compound of Formula (Ia), wherein W is —NH—.Another embodiment provides a compound of Formula (Ia), wherein X isalkyl. Another embodiment provides a compound of Formula (Ia), wherein Xis aryl. Another embodiment provides a compound of Formula (Ia), whereinX is cycloalkylalkyl. Another embodiment provides a compound of Formula(Ia), wherein W is —O— and X is alkyl. Another embodiment provides acompound of Formula (Ia), wherein W is —O— and X is aryl. Anotherembodiment provides a compound of Formula (Ia), wherein W is —O— and Xis cycloalkylalkyl. Another embodiment provides a compound of Formula(Ia), wherein R⁵ and R⁸ are hydrogen. Another embodiment provides acompound of Formula (Ia), wherein R⁵ and R⁸ are hydrogen, and R⁶ isheteroaryl.

One embodiment provides a compound, or a pharmaceutically acceptablesalt thereof, having the structure of Formula (Ib),

-   -   wherein,    -   R² is selected from CH₃;    -   X5 is C—H;    -   X6 is C—R⁶;    -   X7 is C—R⁷;    -   X8 is C—H;    -   R⁶ is hydrogen, or halogen;    -   R⁷ is hydrogen, or halogen;    -   R^(A) is

-   -   X2 is C—H;    -   R¹³ is —Y—Z;    -   Y is selected from a bond, or —CH₂—;    -   Z is selected from —SO₂R²¹, —N(R²²)SO₂R²¹, —SO₂N(R²²)₂,        —N(R²²)SO₂N(R²²)₂, —CON(R²²)₂, —N(R²²)CO₂R²¹, —N(R²²)CON(R²²)₂,        —N(R²²)COR²¹, —OC(O)N(R²²)₂, —OSO₂N(R²²)₂, or —N(R²²)SO₃R²¹;    -   X3 is C—R¹⁴, wherein R¹⁴ is hydrogen, halogen, C₁-C₃ alkyl, or        C₁-C₃ alkoxy;    -   X4 is C—R¹⁵, wherein R¹⁵ is hydrogen, or halogen;    -   R¹⁶ is —W—X, wherein W is a bond, —O—, —S—, or —NH—, and X is        selected from alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl,        heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;    -   each R²¹ is independently selected from alkyl, cycloalkyl,        cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,        heteroaryl, or heteroarylalkyl; and    -   each R²² is independently selected from hydrogen, alkyl,        cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,        heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

Another embodiment provides a compound, or a pharmaceutically acceptablesalt thereof, having the structure of Formula (Ib), wherein R⁶ ishalogen, and R⁷ is hydrogen.

Another embodiment provides a compound, or a pharmaceutically acceptablesalt thereof, having the structure of Formula (Ib), wherein R⁶ ishydrogen, and R⁷ is halogen.

Another embodiment provides a compound, or a pharmaceutically acceptablesalt thereof, having the structure of Formula (Ib), wherein R⁶ ishydrogen, and R⁷ is hydrogen.

Another embodiment provides a compound, or a pharmaceutically acceptablesalt thereof, having the structure of Formula (Ib), wherein Y is —CH2-.Another embodiment provides a compound, or a pharmaceutically acceptablesalt thereof, having the structure of Formula (Ib), wherein Y is —CH₂—,and Z is —SO₂R²¹, or —N(R²²)SO₂R²¹. Another embodiment provides acompound, or a pharmaceutically acceptable salt thereof, having thestructure of Formula (Ib), wherein R²² is hydrogen or methyl.

Another embodiment provides a compound, or a pharmaceutically acceptablesalt thereof, having the structure of Formula (Ib), wherein Y is a bond.Another embodiment provides a compound, or a pharmaceutically acceptablesalt thereof, having the structure of Formula (Ib), wherein Y is a bond,and Z is —N(R²²)SO₂R²¹, or —N(R²²)SO₂N(R²²)₂. Another embodimentprovides a compound, or a pharmaceutically acceptable salt thereof,having the structure of Formula (Ib), wherein Y is a bond, and Z is—SO₂R²¹. Another embodiment provides a compound, or a pharmaceuticallyacceptable salt thereof, having the structure of Formula (Ib), wherein Yis a bond, Z is —SO₂R²¹, and R²¹ is heterocyclyl, or heterocyclylalkyl.Another embodiment provides a compound, or a pharmaceutically acceptablesalt thereof, having the structure of Formula (Ib), wherein Y is a bond,Z is —SO₂R²¹, and R²¹ is alkyl, cycloalkyl, or cycloalkylalkyl. Anotherembodiment provides a compound, or a pharmaceutically acceptable saltthereof, having the structure of Formula (Ib), wherein Y is a bond, Z is—SO₂R²¹, R²¹ is alkyl, and the alkyl is a C₁-C₄ alkyl.

Another embodiment provides a compound, or a pharmaceutically acceptablesalt thereof, having the structure of Formula (Ib), wherein Y is a bond,and Z is —SO₂N(R²²)₂. Another embodiment provides a compound, or apharmaceutically acceptable salt thereof, having the structure ofFormula (Ib), wherein R²² is hydrogen or methyl. Another embodimentprovides a compound, or a pharmaceutically acceptable salt thereof,having the structure of Formula (Ib), wherein Y is a bond, Z is—SO₂N(R²²)₂, and at least one R²² is alkyl, cycloalkyl, or aralkyl.

Another embodiment provides a compound, or a pharmaceutically acceptablesalt thereof, having the structure of Formula (Ib), wherein R²¹ isheterocyclyl, or heterocyclylalkyl. Another embodiment provides acompound, or a pharmaceutically acceptable salt thereof, having thestructure of Formula (Ib), wherein R²² is hydrogen or methyl. Anotherembodiment provides a compound, or a pharmaceutically acceptable saltthereof, having the structure of Formula (Ib), wherein at least one R²²is alkyl, cycloalkyl, or aralkyl.

Another embodiment provides a compound, or a pharmaceutically acceptablesalt thereof, having the structure of Formula (Ib), wherein R²¹ isalkyl, cycloalkyl, or cycloalkylalkyl.

Another embodiment provides a compound, or a pharmaceutically acceptablesalt thereof, having the structure of Formula (Ib), wherein the alkyl isa C₁-C₄ alkyl. Another embodiment provides a compound, or apharmaceutically acceptable salt thereof, having the structure ofFormula (Ib), wherein the C₁-C₄ alkyl is a C₁ alkyl.

Another embodiment provides a compound, or a pharmaceutically acceptablesalt thereof, having the structure of Formula (Ib), wherein R¹⁴ ishydrogen, and R¹⁵ is hydrogen.

Another embodiment provides a compound, or a pharmaceutically acceptablesalt thereof, having the structure of Formula (Ib), wherein W is —NH—.Another embodiment provides a compound, or a pharmaceutically acceptablesalt thereof, having the structure of Formula (Ib), wherein W is —S—.Another embodiment provides a compound, or a pharmaceutically acceptablesalt thereof, having the structure of Formula (Ib), wherein W is a bond.Another embodiment provides a compound, or a pharmaceutically acceptablesalt thereof, having the structure of Formula (Ib), wherein W is —O—.

Another embodiment provides a compound, or a pharmaceutically acceptablesalt thereof, having the structure of Formula (Ib), wherein X is alkyl.Another embodiment provides a compound, or a pharmaceutically acceptablesalt thereof, having the structure of Formula (Ib), wherein W is —NH—,and X is alkyl. Another embodiment provides a compound, or apharmaceutically acceptable salt thereof, having the structure ofFormula (Ib), wherein W is —O— and X is alkyl. Another embodimentprovides a compound, or a pharmaceutically acceptable salt thereof,having the structure of Formula (Ib), wherein W is a bond, and X isalkyl.

Another embodiment provides a compound, or a pharmaceutically acceptablesalt thereof, having the structure of Formula (Ib), wherein X iscycloalkylalkyl. Another embodiment provides a compound, or apharmaceutically acceptable salt thereof, having the structure ofFormula (Ib), wherein W is —NH—, and X is cycloalkylalkyl. Anotherembodiment provides a compound, or a pharmaceutically acceptable saltthereof, having the structure of Formula (Ib), wherein W is —O— and X iscycloalkylalkyl. Another embodiment provides a compound, or apharmaceutically acceptable salt thereof, having the structure ofFormula (Ib), wherein W is a bond, and X is cycloalkylalkyl.

Another embodiment provides a compound, or a pharmaceutically acceptablesalt thereof, having the structure of Formula (Ib), wherein X is aryl.Another embodiment provides a compound, or a pharmaceutically acceptablesalt thereof, having the structure of Formula (Ib), wherein W is —NH—,and X is aryl. Another embodiment provides a compound, or apharmaceutically acceptable salt thereof, having the structure ofFormula (Ib), wherein W is —O—, and X is aryl. Another embodimentprovides a compound, or a pharmaceutically acceptable salt thereof,having the structure of Formula (Ib), wherein W is a bond, and X isaryl.

Another embodiment provides a compound, or a pharmaceutically acceptablesalt thereof, having the structure of Formula (Ib), wherein Y is a bond,Z is —SO₂R²¹, W is —O—, and X is aryl or cycloalkylalkyl. Anotherembodiment provides a compound, or a pharmaceutically acceptable saltthereof, having the structure of Formula (Ib), wherein Y is a bond, Z is—SO₂R²¹, W is —O—, and X is cycloalkylalkyl.

One embodiment provides a compound of Formula (II), or apharmaceutically acceptable salt thereof,

-   -   wherein,    -   R² is alkyl, cycloalkyl, cycloalkylalkyl, heterocyclylalkyl,        aralkyl, or heteroarylalkyl;    -   X6 is C—H or N;    -   X5 is C—R⁵ or N; provided that if X6 is N, then X5 is C—R⁵, and        if X5 is N, then X6 is CH;    -   R⁵ is hydrogen, halogen, —OH, —CN, —OR⁶¹, —NHR⁶¹, —N(R⁶¹)₂,        alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,        heterocyclylalkyl, heteroaryl, or heteroarylalkyl, wherein each        R⁶¹ is independently selected from alkyl, cycloalkyl,        cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,        heteroaryl, or heteroarylalkyl;    -   R⁶ is hydrogen, halogen, —OH, —CN, alkyl, cycloalkyl,        cycloalkylalkyl, amino, alkylamino, dialkylamino,        cycloalkylalkylamino, alkoxy, —S— alkyl, cycloalkylalkoxy,        heterocyclyl, aralkoxy, heteroaryloxy, aryloxy, alkynyloxy, or        —N(H)CO alkyl;    -   R^(A) is

-   -   X2 is N or C—R¹², wherein R¹² is hydrogen, halogen, alkyl, or        alkoxy;    -   R¹³ is —Y—Z;    -   Y is selected from a bond, —CH₂—, or —CH(C₁-C₄alkyl)-;    -   Z is selected from —SO₂R²¹, —N(R²²)SO₂R²¹, —SO₂N(R²²)₂,        —N(R²²)SO₂N(R²²)₂, —CON(R²²)₂, —N(R²²)CO₂R²¹, —N(R²²)CON(R²²)₂,        —N(R²²)COR²¹, —COR²¹, —OC(O)N(R²²)₂, —OSO₂N(R²²)₂, or        —N(R²²)SO₃R²¹;    -   X3 is N or C—R¹⁴, wherein R¹⁴ is hydrogen, halogen, —CN, alkyl,        cycloalkyl, or alkoxy;    -   X4 is N or C—R¹⁵, wherein R¹⁵ is hydrogen, halogen, —CN, alkyl,        alkoxy, aryloxy, aralkyloxy, cycloalkylalkyloxy,        heterocyclyloxy, heteroarylalkyloxy, or alkynyloxy;    -   R¹⁶ is hydrogen, halogen, —N(H)COX, or —W—X, wherein W is a        bond, —O—, —S—, or —NH—, and X is selected from alkyl, aryl,        aralkyl, cycloalkyl, cycloalkylalkyl, alkynyl,        cycloalkylalkynyl, heterocyclyl, heterocyclylalkyl, heteroaryl,        or heteroarylalkyl;    -   each R²¹ is independently selected from alkyl, cycloalkyl,        cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,        heteroaryl, or heteroarylalkyl; and    -   each R²² is independently selected from hydrogen, alkyl,        cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,        heterocyclylalkyl, heteroaryl, or heteroarylalkyl; and    -   provided that when X6 is N, then R⁵ and R⁶ are not hydrogen.

One embodiment provides a compound of Formula (IIa), or apharmaceutically acceptable salt thereof,

-   -   wherein,    -   R² is CH₃, CH₂CH₃, CH₂CF₃, CH₂F, CHF₂, CF₃, CH₂D, CHD₂, or CD₃;    -   X6 is C—H or N;    -   X5 is C—R⁵ or N; provided that if X6 is N, then X5 is C—R⁵, and        if X5 is N, then X6 is CH;    -   R⁵ is hydrogen, halogen, —OH, —CN, —OR⁶¹, —NHR⁶¹, —N(R⁶¹)₂,        alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,        heterocyclylalkyl, heteroaryl, or heteroarylalkyl, wherein each        R⁶¹ is independently selected from alkyl, cycloalkyl,        cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,        heteroaryl, or heteroarylalkyl;    -   R⁶ is hydrogen, halogen, —OH, —CN, alkyl, cycloalkyl,        cycloalkylalkyl, amino, alkylamino, dialkylamino,        cycloalkylalkylamino, alkoxy, or cycloalkylalkoxy;    -   R^(A) is

-   -   X2 is N or C—R¹², wherein R¹² is hydrogen, halogen, alkyl, or        alkoxy;    -   R¹³ is —Y—Z;    -   Y is selected from a bond, or —CH₂—;    -   Z is selected from —SO₂R²¹, —N(R²²)SO₂R²¹, —SO₂N(R²²)₂,        —N(R²²)SO₂N(R²²)₂, —CON(R²²)₂, —N(R²²)CO₂R²¹, —N(R²²)CON(R²²)₂,        —N(R²²)COR²¹, —OC(O)N(R²²)₂, —OSO₂N(R²²)₂, or —N(R²²)SO₃R²¹;    -   X3 is N or C—R¹⁴, wherein R¹⁴ is hydrogen, halogen, —CN, alkyl,        cycloalkyl, or alkoxy;    -   X4 is N or C—R¹⁵, wherein R¹⁵ is hydrogen, halogen, —CN, alkyl,        or alkoxy;    -   R¹⁶ is hydrogen, halogen, or —W—X, wherein W is a bond, —O—,        —S—, or —NH—, and X is selected from alkyl, aryl, aralkyl,        cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl,        heteroaryl, or heteroarylalkyl;    -   each R²¹ is independently selected from alkyl, cycloalkyl,        cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,        heteroaryl, or heteroarylalkyl; and    -   each R²² is independently selected from hydrogen, alkyl,        cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,        heterocyclylalkyl, heteroaryl, or heteroarylalkyl; and    -   provided that when X6 is N, then R⁵ and R⁶ are not hydrogen.

Another embodiment provides a compound of Formula (IIa), wherein X2 isN. Another embodiment provides a compound of Formula (IIa), wherein X3is N. Another embodiment provides a compound of Formula (IIa), whereinX4 is N. Another embodiment provides a compound of Formula (IIa),wherein X2 and X3 are N. Another embodiment provides a compound ofFormula (IIa), wherein X2 is C—R¹², X3 is C—R¹⁴, and X4 is C—R¹⁵.

Another embodiment provides a compound of Formula (IIa), wherein R² isCH₃. Another embodiment provides a compound of Formula (IIa), wherein X6is C—H. Another embodiment provides a compound of Formula (IIa), whereinX6 is N. Another embodiment provides a compound of Formula (IIa),wherein X5 is C—R⁵. Another embodiment provides a compound of Formula(IIa), wherein X5 is N. Another embodiment provides a compound ofFormula (IIa), wherein R⁵ is hydrogen, halogen, or alkyl. Anotherembodiment provides a compound of Formula (IIa), wherein R⁶ is hydrogen,halogen, or alkyl.

Another embodiment provides a compound of Formula (IIa), wherein Y is abond. Another embodiment provides a compound of Formula (IIa), wherein Yis a —CH₂—. Another embodiment provides a compound of Formula (IIa),wherein Z is —SO₂R²¹. Another embodiment provides a compound of Formula(IIa), wherein Z is —N(R²²)SO₂R²¹. Another embodiment provides acompound of Formula (IIa), wherein Z is —SO₂N(R²²)₂. Another embodimentprovides a compound of Formula (IIa), wherein Z is —N(R²²)SO₂N(R²²)₂.Another embodiment provides a compound of Formula (IIa), wherein Z is—CON(R²²)₂. Another embodiment provides a compound of Formula (IIa),wherein Z is —N(R²²)CO₂R²¹. Another embodiment provides a compound ofFormula (IIa), wherein Z is —N(R²²)CON(R²²)₂. Another embodimentprovides a compound of Formula (IIa), wherein R²¹ is alkyl, cycloalkyl,or cycloalkylalkyl. Another embodiment provides a compound of Formula(IIa), wherein R²¹ is alkyl. Another embodiment provides a compound ofFormula (IIa), wherein R¹⁴ is hydrogen, halogen, or alkyl. Anotherembodiment provides a compound of Formula (IIa), wherein X4 is C—R¹⁵.Another embodiment provides a compound of Formula (IIa), wherein W is—O—. Another embodiment provides a compound of Formula (IIa), wherein Wis —NH—. Another embodiment provides a compound of Formula (IIa),wherein X is alkyl. Another embodiment provides a compound of Formula(IIa), wherein X is aryl. Another embodiment provides a compound ofFormula (IIa), wherein X is cycloalkylalkyl. Another embodiment providesa compound of Formula (IIa), wherein W is —O— and X is alkyl. Anotherembodiment provides a compound of Formula (IIa), wherein W is —O— and Xis aryl. Another embodiment provides a compound of Formula (IIa),wherein W is —O— and X is cycloalkylalkyl. Another embodiment provides acompound of Formula (IIa), wherein the R⁶ is CD3.

One embodiment provides a compound of Formula (IIb), or apharmaceutically acceptable salt thereof,

-   -   wherein,    -   R² is CH₃;    -   X6 is C—H;    -   X5 is C—R⁵;    -   R⁵ is hydrogen;    -   R⁶ is halogen or alkyl;    -   R^(A) is

-   -   X2 is N;    -   R¹³ is —Y—Z;    -   Y is selected from a bond, or —CH₂—;    -   Z is selected from —SO₂R²¹, —N(R²²)SO₂R²¹, —SO₂N(R²²)₂,        —N(R²²)SO₂N(R²²)₂, —CON(R²²)₂, —N(R²²)CO₂R²¹, —N(R²²)CON(R²²)₂,        —N(R²²)COR²¹, —OC(O)N(R²²)₂, —OSO₂N(R²²)₂, or —N(R²²)SO₃R²¹;    -   X3 is N;    -   X4 is C—R¹⁵, wherein R¹⁵ is hydrogen, halogen, —CN, alkyl, or        alkoxy;    -   R¹⁶ is —W—X, wherein W is a bond, —O—, —S—, or —NH—, and X is        selected from alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl,        heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;    -   each R²¹ is independently selected from alkyl, cycloalkyl,        cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,        heteroaryl, or heteroarylalkyl; and    -   each R²² is independently selected from hydrogen, alkyl,        cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,        heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

Another embodiment provides a compound of Formula (IIb), wherein R⁶ ishalogen. Another embodiment provides a compound of Formula (IIb),wherein R⁶ is alkyl. Another embodiment provides a compound of Formula(IIb), wherein R⁶ is C₁-C₃ alkyl. Another embodiment provides a compoundof Formula (IIb), wherein R⁶ is C₁ alkyl.

Another embodiment provides a compound of Formula (IIb), wherein Y is abond. Another embodiment provides a compound of Formula (IIb), wherein Yis a —CH₂—. Another embodiment provides a compound of Formula (IIb),wherein Z is —SO₂R²¹. Another embodiment provides a compound of Formula(IIb), wherein Z is —N(R²²)SO₂R²¹. Another embodiment provides acompound of Formula (IIb), wherein Z is —SO₂N(R²²)₂. Another embodimentprovides a compound of Formula (IIb), wherein Z is —N(R²²)SO₂N(R²²)₂.Another embodiment provides a compound of Formula (IIb), wherein Z is—CON(R²²)₂. Another embodiment provides a compound of Formula (IIb),wherein Z is —N(R²²)CO₂R²¹. Another embodiment provides a compound ofFormula (IIb), wherein Z is —N(R²²)CON(R²²)₂. Another embodimentprovides a compound of Formula (IIb), wherein R²¹ is alkyl, cycloalkyl,or cycloalkylalkyl. Another embodiment provides a compound of Formula(IIb), wherein R²¹ is alkyl. Another embodiment provides a compound ofFormula (IIb), wherein R²¹ is C₁-C₂ alkyl.

Another embodiment provides a compound of Formula (IIb), wherein W is—O—. Another embodiment provides a compound of Formula (IIb), wherein Wis —NH—. Another embodiment provides a compound of Formula (IIb),wherein W is a bond. Another embodiment provides a compound of Formula(IIb), wherein X is alkyl. Another embodiment provides a compound ofFormula (IIb), wherein X is aryl. Another embodiment provides a compoundof Formula (IIb), wherein X is cycloalkylalkyl. Another embodimentprovides a compound of Formula (IIb), wherein W is —O— and X is alkyl.Another embodiment provides a compound of Formula (IIb), wherein W is—O— and X is aryl. Another embodiment provides a compound of Formula(IIb), wherein W is —O— and X is cycloalkylalkyl. Another embodimentprovides a compound of Formula (IIb), wherein W is a bond and X isalkyl. Another embodiment provides a compound of Formula (IIb), whereinW is a bond and X is aryl. Another embodiment provides a compound ofFormula (IIb), wherein W is a bond and X is cycloalkylalkyl. Anotherembodiment provides a compound of Formula (IIb), wherein the R⁶ is CD₃.

One embodiment provides a compound of Formula (III), or apharmaceutically acceptable salt thereof,

-   -   wherein,    -   R² is CH₃, CH₂CH₃, CH₂CF₃, CH₂F, CHF₂, CF₃, CH₂D, CHD₂, or CD₃;    -   X1 is C—H or N;    -   ring B is an optionally substituted 5- or 6-membered        heterocyclic ring containing at least one oxygen or nitrogen        atom;    -   R^(A) is

-   -   X2 is N or C—R¹², wherein R¹² is hydrogen, halogen, alkyl, or        alkoxy;    -   R¹³ is —Y—Z;    -   Y is selected from a bond, —CH₂—, or —CH(C₁-C₄ alkyl)-;    -   Z is selected from —SO₂R²¹, —N(R²²)SO₂R²¹, —SO₂N(R²²)₂,        —N(R²²)SO₂N(R²²)₂, —CON(R²²)₂, —N(R²²)CO₂R²¹, —N(R²²)CON(R²²)₂,        —N(R²²)COR²¹, —OC(O)N(R²²)₂, —OSO₂N(R²²)₂, or —N(R²²)SO₃R²¹;    -   X3 is N or C—R¹⁴, wherein R¹⁴ is hydrogen, halogen, —CN, alkyl,        cycloalkyl, or alkoxy; or optionally when X4 is C—R¹⁵, R¹⁴ and        R¹⁵ connect to form a ring;    -   X4 is N or C—R¹⁵, wherein R¹⁵ is hydrogen, halogen, —CN, alkyl,        or alkoxy;    -   R¹⁶ is hydrogen, halogen, or —W—X, wherein W is a bond, —O—,        —S—, or —NH—, and X is selected from alkyl, alkynyl, aryl,        aralkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkynyl,        heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;        or optionally when X4 is C—R¹⁵, R¹⁶ and R¹⁵ connect to form a        ring;    -   each R²¹ is independently selected from alkyl, cycloalkyl,        cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,        heteroaryl, or heteroarylalkyl; and    -   each R²² is independently selected from hydrogen, alkyl,        cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,        heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

Another embodiment provides a compound of Formula (III), wherein X2 isN. Another embodiment provides a compound of Formula (III), wherein X3is N. Another embodiment provides a compound of Formula (III), whereinX4 is N. Another embodiment provides a compound of Formula (III),wherein X2 and X3 are N. Another embodiment provides a compound ofFormula (III), wherein X2 is C—R¹², X3 is C—R¹⁴, and X4 is C—R¹⁵.

Another embodiment provides a compound of Formula (III), having thestructure of Formula (IIIa):

-   -   wherein,    -   ring B is a 6-membered ring having one nitrogen atom;    -   R²³ is selected from alkyl, aryl, aralkyl, cycloalkyl,        cycloalkylalkyl, —COR²⁴, —CO₂R²⁴, —CONH(R²⁴), CON(R²⁴)₂, or        —SO₂R²⁴; and    -   each R²⁴ is independently selected from alkyl, aryl, aralkyl,        cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl,        heteroaryl, or heteroarylalkyl.

Another embodiment provides a compound of Formula (III), wherein R² isCH₃. Another embodiment provides a compound of Formula (III), wherein X1is C—H. Another embodiment provides a compound of Formula (III), whereinX1 is N.

Another embodiment provides a compound of Formula (III), wherein Y is abond. Another embodiment provides a compound of Formula (III), wherein Yis a —CH₂—. Another embodiment provides a compound of Formula (III),wherein Z is —SO₂R²¹. Another embodiment provides a compound of Formula(III), wherein Z is —N(R²²)SO₂R²¹. Another embodiment provides acompound of Formula (III), wherein Z is —SO₂N(R²²)₂. Another embodimentprovides a compound of Formula (III), wherein Z is —N(R²²)SO₂N(R²²)₂.Another embodiment provides a compound of Formula (III), wherein Z is—CON(R²²)₂. Another embodiment provides a compound of Formula (III),wherein Z is —N(R²²)CO2R²¹. Another embodiment provides a compound ofFormula (III), wherein Z is —N(R²²)CON(R²²)₂. Another embodimentprovides a compound of Formula (III), wherein R²¹ is alkyl, cycloalkyl,or cycloalkylalkyl. Another embodiment provides a compound of Formula(III), wherein R²¹ is alkyl. Another embodiment provides a compound ofFormula (III), wherein R¹⁴ is hydrogen, halogen, or alkyl. Anotherembodiment provides a compound of Formula (III), wherein X4 is C—R¹⁵.Another embodiment provides a compound of Formula (III), wherein W is—O—. Another embodiment provides a compound of Formula (III), wherein Wis —NH—. Another embodiment provides a compound of Formula (III),wherein X is alkyl. Another embodiment provides a compound of Formula(III), wherein X is alkynyl. Another embodiment provides a compound ofFormula (III), wherein X is aryl. Another embodiment provides a compoundof Formula (III), wherein X is cycloalkylalkyl. Another embodimentprovides a compound of Formula (III), wherein X is cycloalkylalkynyl.Another embodiment provides a compound of Formula (III), wherein W is—O— and X is alkyl. Another embodiment provides a compound of Formula(III), wherein W is —O— and X is alkynyl. Another embodiment provides acompound of Formula (III), wherein W is —O— and X is aryl. Anotherembodiment provides a compound of Formula (III), wherein W is —O— and Xis cycloalkylalkyl. Another embodiment provides a compound of Formula(III), wherein W is —O— and X is cycloalkylalkynyl.

One embodiment provides a compound of Formula (IV), or apharmaceutically acceptable salt thereof,

-   -   wherein,    -   Q is N and T is C, or Q is C and T is N;    -   Ring B is an optionally substituted 5-membered aromatic        nitrogen-containing heteroaryl ring containing one or more        nitrogen atoms;    -   R² is selected from CH₃, CH₂CH₃, CH₂CF₃, CH₂F, CHF₂, CF₃, CH₂D,        CHD₂, or CD₃;    -   X1 is C—H or N;    -   R^(A) is

-   -   X2 is N or C—R¹², wherein R¹² is hydrogen, halogen, alkyl, or        alkoxy;    -   R¹³ is —Y—Z;    -   Y is selected from a bond, or —CH₂—;    -   Z is selected from —SO₂R²¹, —N(R²²)SO₂R²¹, —SO₂N(R²²)₂,        —N(R²²)SO₂N(R²²)₂, —CON(R²²)₂, —N(R²²)CO₂R²¹, —N(R²²)CON(R²²)₂,        —N(R²²)COR²¹, —OC(O)N(R²²)₂, —OSO₂N(R²²)₂, or —N(R²²)SO₃R²¹;    -   X3 is N or C—R¹⁴, wherein R¹⁴ is hydrogen, halogen, —CN, alkyl,        cycloalkyl, or alkoxy;    -   X4 is N or C—R¹⁵, wherein R¹⁵ is hydrogen, halogen, —CN, alkyl,        or alkoxy;    -   R¹⁶ is hydrogen, halogen, or —W—X, wherein W is a bond, —O—,        —S—, or —NH—, and X is selected from alkyl, aryl, aralkyl,        cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl,        heteroaryl, or heteroarylalkyl;    -   each R²¹ is independently selected from alkyl, cycloalkyl,        cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,        heteroaryl, or heteroarylalkyl; and each R²² is independently        selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl,        aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or        heteroarylalkyl.

Another embodiment provides a compound of Formula (IV), wherein X2 is N.Another embodiment provides a compound of Formula (IV), wherein X3 is N.Another embodiment provides a compound of Formula (IV), wherein X4 is N.Another embodiment provides a compound of Formula (IV), wherein X2 andX3 are N. Another embodiment provides a compound of Formula (IV),wherein X2 is C—R¹², X3 is C—R¹⁴, and X4 is C—R¹⁵.

Another embodiment provides a compound of Formula (IV), wherein thecompound of Formula (IV) is selected from the group:

Another embodiment provides a compound of Formula (IV), wherein thecompound of Formula (IV) has the structure:

Another embodiment provides a compound of Formula (IV), wherein Q is Nand T is C. Another embodiment provides a compound of Formula (IV),wherein Q is C and T is N. Another embodiment provides a compound ofFormula (IV), wherein R² is CH₃. Another embodiment provides a compoundof Formula (IV), wherein X1 is C—H. Another embodiment provides acompound of Formula (IV), wherein X1 is N.

Another embodiment provides a compound of Formula (IV), wherein Y is abond. Another embodiment provides a compound of Formula (IV), wherein Yis a —CH₂—. Another embodiment provides a compound of Formula (IV),wherein Z is —SO₂R²¹. Another embodiment provides a compound of Formula(IV), wherein Z is —N(R²²)SO₂R²¹. Another embodiment provides a compoundof Formula (IV), wherein Z is —SO₂N(R²²)₂. Another embodiment provides acompound of Formula (IV), wherein Z is —N(R²²)SO₂N(R²²)₂. Anotherembodiment provides a compound of Formula (IV), wherein Z is —CON(R²²)₂.Another embodiment provides a compound of Formula (IV), wherein Z is—N(R²²)CO2R²¹. Another embodiment provides a compound of Formula (IV),wherein Z is —N(R²²)CON(R²²)₂. Another embodiment provides a compound ofFormula (IV), wherein R²¹ is alkyl, cycloalkyl, or cycloalkylalkyl.Another embodiment provides a compound of Formula (IV), wherein R²¹ isalkyl. Another embodiment provides a compound of Formula (IV), whereinR¹⁴ is hydrogen, halogen, or alkyl. Another embodiment provides acompound of Formula (IV), wherein X4 is C—R¹⁵. Another embodimentprovides a compound of Formula (IV), wherein W is —O—. Anotherembodiment provides a compound of Formula (IV), wherein W is —NH—.Another embodiment provides a compound of Formula (IV), wherein X isalkyl. Another embodiment provides a compound of Formula (IV), wherein Xis aryl. Another embodiment provides a compound of Formula (IV), whereinX is cycloalkylalkyl. Another embodiment provides a compound of Formula(IV), wherein W is —O— and X is alkyl. Another embodiment provides acompound of Formula (IV), wherein W is —O— and X is aryl. Anotherembodiment provides a compound of Formula (IV), wherein W is —O— and Xis cycloalkylalkyl.

Another embodiment provides a compound of Formula (V), or apharmaceutically acceptable salt thereof,

-   -   wherein,    -   R² is selected from CH₃, CH₂CH₃, CH₂CF₃, CH₂F, CHF₂, CF₃, CH₂D,        CHD₂, or CD₃;    -   X5 is C—R⁵ or N;    -   X6 is C—R⁶ or N;    -   X7 is C—R⁷ or N;    -   X8 is C—R⁸ or N; wherein no more than two of X5, X6, X7, or X8        may be N;    -   R⁵ is hydrogen, halogen, —OH, —CN, —OR⁶¹, —NHR⁶¹, —N(R⁶¹)₂,        alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,        heterocyclylalkyl, heteroaryl, or heteroarylalkyl, wherein each        R⁶¹ is independently selected from alkyl, cycloalkyl,        cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,        heteroaryl, or heteroarylalkyl;    -   R⁶ is hydrogen, halogen, —OH, —CN, —OR⁶¹, —NHR⁶¹, —N(R⁶¹)₂,        alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,        heterocyclylalkyl, heteroaryl, or heteroarylalkyl, wherein each        R⁶¹ is independently selected from alkyl, cycloalkyl,        cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,        heteroaryl, or heteroarylalkyl;    -   R⁷ is hydrogen, halogen, —OH, —CN, —OR⁶¹, —NHR⁶¹, —N(R⁶¹)₂,        alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,        heterocyclylalkyl, heteroaryl, or heteroarylalkyl, wherein each        R⁶¹ is independently selected from alkyl, cycloalkyl,        cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,        heteroaryl, or heteroarylalkyl;    -   R⁸ is hydrogen, halogen, or alkyl;    -   R^(A) is

-   -   X2 is N or C—R¹², wherein R¹² is hydrogen, halogen, alkyl, or        alkoxy;    -   R¹³ is —Y—Z;    -   Y is selected from a bond, or —CH₂—;    -   Z is selected from —SO₂R²¹, —N(R²²)SO₂R²¹, —SO₂N(R²²)₂,        —N(R²²)SO₂N(R²²)₂, —CON(R²²)₂, —N(R²²)CO₂R²¹, —N(R²²)CON(R²²)₂,        —N(R²²)COR²¹, —OC(O)N(R²²)₂, —OSO₂N(R²²)₂, or —N(R²²)SO₃R²¹;    -   X3 is N or C—R¹⁴, wherein R¹⁴ is hydrogen, halogen, alkyl,        cycloalkyl, or alkoxy;    -   X4 is N or C—R¹⁵, wherein R¹⁵ is hydrogen, halogen, alkyl, or        alkoxy;    -   R¹⁶ is hydrogen, halogen, or —W—X, wherein W is a bond, —O—,        —S—, or —NH—, and X is selected from alkyl, aryl, aralkyl,        cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl,        heteroaryl, or heteroarylalkyl;    -   each R²¹ is independently selected from alkyl, cycloalkyl,        cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,        heteroaryl, or heteroarylalkyl; and    -   each R²² is independently selected from hydrogen, alkyl,        cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,        heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

Another embodiment provides a compound of Formula (V), wherein X2 is N.Another embodiment provides a compound of Formula (V), wherein X3 is N.Another embodiment provides a compound of Formula (V), wherein X4 is N.Another embodiment provides a compound of Formula (V), wherein X2 and X3are N. Another embodiment provides a compound of Formula (V), wherein X2is C—R¹², X3 is C—R¹⁴, and X4 is C—R¹⁵.

Another embodiment provides a compound of Formula (V), wherein R² isCH₃. Another embodiment provides a compound of Formula (V), wherein R²is CD₃. Another embodiment provides a compound of Formula (V), whereinX5 is N. Another embodiment provides a compound of Formula (V), whereinX6 is N. Another embodiment provides a compound of Formula (V), whereinX7 is N. Another embodiment provides a compound of Formula (V), whereinX8 is N. Another embodiment provides a compound of Formula (V), whereinnone of X5, X6, X7, or X8 is N. Another embodiment provides a compoundof Formula (V), wherein R⁵ and R⁸ are hydrogen. Another embodimentprovides a compound of Formula (V), wherein R⁵, R⁶, R⁷ and R⁸ arehydrogen. Another embodiment provides a compound of Formula (V), whereinR⁷ is a halogen. Another embodiment provides a compound of Formula (V),wherein R⁶ is a halogen. Another embodiment provides a compound ofFormula (V), wherein R⁶ is a heteroaryl. Another embodiment provides acompound of Formula (V), wherein R⁶ is an aryl. Another embodimentprovides a compound of Formula (V), wherein R⁶ is an alkyl. Anotherembodiment provides a compound of Formula (V), wherein R6 is an aryl.

Another embodiment provides a compound of Formula (V), wherein Y is abond. Another embodiment provides a compound of Formula (V), wherein Yis a —CH₂—. Another embodiment provides a compound of Formula (V),wherein Z is —SO₂R²¹. Another embodiment provides a compound of Formula(V), wherein Z is —N(R²²)SO₂R²¹. Another embodiment provides a compoundof Formula (V), wherein Z is —SO₂N(R²²)₂. Another embodiment provides acompound of Formula (V), wherein Z is —N(R²²)SO₂N(R²²)₂. Anotherembodiment provides a compound of Formula (V), wherein Z is —CON(R²²)₂.Another embodiment provides a compound of Formula (V), wherein Z is—N(R²²)CO₂R21. Another embodiment provides a compound of Formula (V),wherein Z is —N(R²²)CON(R²²)₂. Another embodiment provides a compound ofFormula (V), wherein R²¹ is alkyl, cycloalkyl, or cycloalkylalkyl.Another embodiment provides a compound of Formula (V), wherein R²¹ isalkyl. Another embodiment provides a compound of Formula (V), whereinR¹⁴ is hydrogen, halogen, or alkyl. Another embodiment provides acompound of Formula (V), wherein X4 is C—R¹⁵. Another embodimentprovides a compound of Formula (V), wherein W is —O—. Another embodimentprovides a compound of Formula (V), wherein W is —NH—. Anotherembodiment provides a compound of Formula (V), wherein X is alkyl.Another embodiment provides a compound of Formula (V), wherein X isaryl. Another embodiment provides a compound of Formula (V), wherein Xis cycloalkylalkyl. Another embodiment provides a compound of Formula(V), wherein W is —O— and X is alkyl. Another embodiment provides acompound of Formula (V), wherein W is —O— and X is aryl. Anotherembodiment provides a compound of Formula (V), wherein W is —O— and X iscycloalkylalkyl. Another embodiment provides a compound of Formula (V),wherein R⁵ and R⁸ are hydrogen. Another embodiment provides a compoundof Formula (V), wherein R⁵ and R⁸ are hydrogen, and R⁶ is heteroaryl.

One embodiment provides a compound of Formula (VIa), or apharmaceutically acceptable salt thereof,

-   -   wherein,    -   R² is CH₃ or CD₃;    -   R⁵ is hydrogen or CH₃;    -   R⁶ is hydrogen, CH₃, Cl, F, Br, NH₂, N(CH₃)₂, NH(alkyl), or CD₃;    -   R^(A) is

-   -   R¹³ is —Y—Z;    -   Y is selected from a bond or —CH₂—;    -   Z is —SO₂R²¹;    -   R¹⁴ is hydrogen, F, or Cl;    -   R¹⁶ is —W—X, wherein W is —O— or —NH—, and X is selected from        CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, cyclopropyl, cyclobutyl,        cyclopentyl, cyclohexyl, CH₂-(cyclopropyl), C₆H₅,        4-fluoro(C₆H₄), 2,4-difluoro(C₆H₃), 2-fluoro(C₆H₄),        4-tetrahydropyranyl, 3-tetrahydropyranyl, oxolan-3-yl,        4,4-difluorocyclohexyl, and 4-hydroxycyclohexyl; and    -   each R²¹ is CH₃ or CH₂CH₃.

Another embodiment provides a compound of Formula (VIa), wherein Y is abond. Another embodiment provides a compound of Formula (VIa), wherein Yis —CH₂—. Another embodiment provides a compound of Formula (VIa),wherein W is —O—. Another embodiment provides a compound of Formula(VIa), wherein W is —NH—. Another embodiment provides a compound ofFormula (VIa), wherein R² is CH₃. Another embodiment provides a compoundof Formula (VIa), wherein R² is CD₃.

One embodiment provides a compound of Formula (VIb), or apharmaceutically acceptable salt thereof,

-   -   wherein,    -   R² is CH₃ or CD₃;    -   R⁵ is hydrogen or CH₃;    -   R⁶ is hydrogen, CH₃, Cl, F, Br, NH₂, N(CH₃)₂, NH(alkyl), or CD₃;    -   R^(A) is

-   -   R¹³ is —NHSO₂R²¹;    -   R¹⁴ is hydrogen, F, or Cl;    -   R¹⁶ is —W—X, wherein W is —O— or —NH—, and X is selected from        CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, cyclopropyl, cyclobutyl,        cyclopentyl, cyclohexyl, CH₂-(cyclopropyl), C₆H₅,        4-fluoro(C₆H₄), 2,4-difluoro(C₆H₃), 2-fluoro(C₆H₄),        4-tetrahydropyranyl, 3-tetrahydropyranyl, oxolan-3-yl,        4,4-difluorocyclohexyl, and 4-hydroxycyclohexyl; and    -   each R²¹ is CH₃ or CH₂CH₃.    -   Another embodiment provides a compound of Formula (VIb), wherein        W is —O—. Another embodiment provides a compound of Formula        (VIb), wherein W is —NH—. Another embodiment provides a compound        of Formula (VIb), wherein R² is CH₃. Another embodiment provides        a compound of Formula (VIb), wherein R² is CD₃.

One embodiment provides a compound of Formula (VIc), or apharmaceutically acceptable salt thereof,

-   -   wherein,    -   R² is CH₃ or CD₃;    -   R⁵ is hydrogen or CH₃;    -   R⁶ is hydrogen, CH₃, Cl, F, Br, NH₂, N(CH₃)₂, NH(alkyl), or CD₃;    -   R^(A) is

-   -   R¹³ is —Y—Z;    -   Y is selected from a bond or —CH₂—;    -   Z is —SO₂R²¹;    -   R¹⁶ is —W—X, wherein W is —O— or —NH—, and X is selected from        CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, cyclopropyl, cyclobutyl,        cyclopentyl, cyclohexyl, CH₂-(cyclopropyl), C₆H₅,        4-fluoro(C₆H₄), 2,4-difluoro(C₆H₃), 2-fluoro(C₆H₄),        4-tetrahydropyranyl, 3-tetrahydropyranyl, oxolan-3-yl,        4,4-difluorocyclohexyl, and 4-hydroxycyclohexyl; and    -   each R²¹ is CH₃ or CH₂CH₃.

Another embodiment provides a compound of Formula (VIc), wherein Y is abond. Another embodiment provides a compound of Formula (VIc), wherein Yis —CH2-. Another embodiment provides a compound of Formula (VIc),wherein W is —O—. Another embodiment provides a compound of Formula(VIc), wherein W is —NH—. Another embodiment provides a compound ofFormula (VIc), wherein R² is CH₃. Another embodiment provides a compoundof Formula (VIc), wherein R² is CD₃.

One embodiment provides a compound of Formula (VId), or apharmaceutically acceptable salt thereof,

-   -   wherein,    -   R² is CH₃ or CD₃;    -   R⁵ is hydrogen or CH₃;    -   R⁶ is hydrogen, CH₃, Cl, F, Br, NH₂, N(CH₃)₂, NH(alkyl), or CD₃;    -   R^(A) is

-   -   R¹³ is —NHSO₂R²¹;    -   R¹⁶ is —W—X, wherein W is —O— or —NH—, and X is selected from        CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, cyclopropyl, cyclobutyl,        cyclopentyl, cyclohexyl, CH₂-(cyclopropyl), C₆H₅,        4-fluoro(C₆H₄), 2,4-difluoro(C₆H₃), 2-fluoro(C₆H₄),        4-tetrahydropyranyl, 3-tetrahydropyranyl, oxolan-3-yl,        4,4-difluorocyclohexyl, and 4-hydroxycyclohexyl; and    -   each R²¹ is CH₃ or CH₂CH₃.

Another embodiment provides a compound of Formula (VId), wherein W is—O—. Another embodiment provides a compound of Formula (VId), wherein Wis —NH—. Another embodiment provides a compound of Formula (VId),wherein R2 is CH3. Another embodiment provides a compound of Formula(VId), wherein R2 is CD₃.

One embodiment provides a compound of Formula (VIe), or apharmaceutically acceptable salt thereof,

-   -   wherein,    -   R² is hydrogen, CH₃, or CHF₂;    -   R⁶ is CH₃, CD₃, cyclopropyl, NH(CH₃), NH(CH₂CH₃), F, or Cl;    -   R^(A) is

-   -   R¹³ is —Y—Z;    -   Y is selected from —NH— or —CH₂—;    -   Z is selected from —SO₂R²¹;    -   R¹⁴ is hydrogen, CH₃, or F;    -   X9 is N or CH;    -   R¹⁶ is —W—X, wherein W is —O— or —NH—, and X is selected from        CH₃, CH₂CH₃, CH₂CH₂CH₃, CH₂-(cyclopropyl), CH₂CH₂CFH₂,        2,4-difluoro(C₆H₃), 2,3-difluoro(C₆H₃), 2-chloro-4-fluoro(C₆H₃),        2-fluoro(C₆H₄), and 2-chloro(C₆H₄); and    -   each R²¹ is independently selected from CH₃, CH₂CH₃, CH₂CH₂CH₃,        CH₂CH₂CHF₂, CH₂-(cyclopropyl), and cyclopropyl.

Another embodiment provides a compound of Formula (VIe), wherein Y is—NH—. Another embodiment provides a compound of Formula (VIe), wherein Yis —CH₂—. Another embodiment provides a compound of Formula (VIe),wherein W is —O—. Another embodiment provides a compound of Formula(VIe), wherein W is —NH—. Another embodiment provides a compound ofFormula (VIe), wherein X9 is N. Another embodiment provides a compoundof Formula (VIe), wherein X9 is CH. Another embodiment provides acompound of Formula (VIe), wherein R² is hydrogen. Another embodimentprovides a compound of Formula (VIe), wherein R² is CH₃. Anotherembodiment provides a compound of Formula (VIe), wherein R² is CHF₂.

One embodiment provides a compound of Formula (VII), or apharmaceutically acceptable salt thereof,

-   -   wherein,    -   R² is CH₃, CH₂CH₃, CH₂CF₃, CH₂F, CHF₂, CF₃, CH₂D, CHD₂, or CD₃;    -   X6 is C—H or N;    -   X5 is C—R⁵ or N; provided that if X6 is N, then X5 is C—R⁵, and        if X5 is N, then X6 is CH;    -   R⁵ is hydrogen, halogen, —OH, —CN, —OR⁶¹, —NHR⁶¹, —N(R⁶¹)₂,        alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,        heterocyclylalkyl, heteroaryl, or heteroarylalkyl, wherein each        R⁶¹ is independently selected from alkyl, cycloalkyl,        cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,        heteroaryl, or heteroarylalkyl;    -   R⁶ is hydrogen, halogen, —OH, —CN, alkyl, alkynyl, cycloalkyl,        cycloalkylalkyl, cycloalkylalkynyl, amino, alkylamino,        dialkylamino, heterocyclyl, cycloalkylalkylamino, alkoxy,        cycloalkyloxy, cycloalkylalkoxy, alkyl-S—, cycloalkyl-S—, and        cycloalkylalkyl-S—;    -   R^(A) is

-   -   X2 is N or C—R¹², wherein R¹² is hydrogen, halogen, alkyl, or        alkoxy;    -   R¹³ is —Y—Z;    -   Y is selected from a bond, —CH₂—, or —CH(C₁-C₄ alkyl)-;    -   Z is selected from —SO₂R²¹, —N(R²²)SO₂R²¹, —SO₂N(R²²)₂,        —N(R²²)SO₂N(R²²)₂, —CON(R²²)₂, —N(R²²)CO₂R²¹, —N(R²²)CON(R²²)₂,        vN(R²²)COR²¹, —OC(O)N(R²²)₂, —OSO₂N(R²²)₂, or —N(R²²)SO₃R²¹;    -   X3 is N or C—R¹⁴, wherein R¹⁴ is hydrogen, halogen, —CN, alkyl,        cycloalkyl, or alkoxy; or optionally when X4 is C—R¹⁵, R¹⁴ and        R¹⁵ connect to form a ring;    -   X4 is N or C—R¹⁵, wherein R¹⁵ is hydrogen, halogen, —CN, alkyl,        or alkoxy;    -   R¹⁶ is hydrogen, halogen, or —W—X, wherein W is a bond, —O—,        —S—, or —NH—, and X is selected from alkyl, alkynyl, aryl,        aralkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkynyl,        heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;        or optionally when X4 is C—R¹⁵, R¹⁶ and R¹⁵ connect to form a        ring;    -   each R²¹ is independently selected from alkyl, cycloalkyl,        cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,        heteroaryl, or heteroarylalkyl; and    -   each R²² is independently selected from hydrogen, alkyl,        cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,        heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

Another embodiment provides a compound of Formula (VII), wherein X2 isN. Another embodiment provides a compound of Formula (VII), wherein X3is N. Another embodiment provides a compound of Formula (VII), whereinX4 is N. Another embodiment provides a compound of Formula (VII),wherein X2 and X3 are N. Another embodiment provides a compound ofFormula (VII), wherein X2 is C—R¹², X3 is C—R¹⁴, and X4 is C—R¹⁵.

Another embodiment provides a compound of Formula (VII), wherein R² isCH₃. Another embodiment provides a compound of Formula (VII), wherein X6is C—H. Another embodiment provides a compound of Formula (VII), whereinX6 is N. Another embodiment provides a compound of Formula (VII),wherein X5 is C—R⁵. Another embodiment provides a compound of Formula(VII), wherein X5 is N. Another embodiment provides a compound ofFormula (VII), wherein R⁵ is hydrogen, halogen, or alkyl. Anotherembodiment provides a compound of Formula (VII), wherein R⁶ is hydrogen,halogen, or alkyl. Another embodiment provides a compound of Formula(VII), wherein R⁶ is heterocyclyl. Another embodiment provides acompound of Formula (VII), wherein R⁶ is cycloalkylalkynyl. Anotherembodiment provides a compound of Formula (VII), wherein R⁶ is alkoxy,cycloalkyloxy, or cycloalkylalkoxy.

Another embodiment provides a compound of Formula (VII), wherein Y is abond. Another embodiment provides a compound of Formula (VII), wherein Yis a —CH₂—. Another embodiment provides a compound of Formula (VII),wherein Z is —SO₂R²¹. Another embodiment provides a compound of Formula(VII), wherein Z is —N(R²²)SO₂R²¹. Another embodiment provides acompound of Formula (VII), wherein Z is —SO₂N(R²²)₂. Another embodimentprovides a compound of Formula (VII), wherein Z is —N(R²²)SO₂N(R²²)₂.Another embodiment provides a compound of Formula (VII), wherein Z is—CON(R²²)₂. Another embodiment provides a compound of Formula (VII),wherein Z is —N(R²²)CO₂R²¹. Another embodiment provides a compound ofFormula (VII), wherein Z is —N(R²²)CON(R²²)₂. Another embodimentprovides a compound of Formula (VII), wherein R²¹ is alkyl, cycloalkyl,or cycloalkylalkyl. Another embodiment provides a compound of Formula(VII), wherein R²¹ is alkyl. Another embodiment provides a compound ofFormula (VII), wherein R¹⁴ is hydrogen, halogen, or alkyl. Anotherembodiment provides a compound of Formula (VII), wherein X4 is C—R¹⁵.Another embodiment provides a compound of Formula (VII), wherein W is—O—. Another embodiment provides a compound of Formula (VII), wherein Wis —NH—. Another embodiment provides a compound of Formula (VII),wherein X is alkyl. Another embodiment provides a compound of Formula(VII), wherein X is alkynyl. Another embodiment provides a compound ofFormula (VII), wherein X is aryl. Another embodiment provides a compoundof Formula (VII), wherein X is cycloalkylalkyl. Another embodimentprovides a compound of Formula (VII), wherein X is cycloalkylalkynyl.Another embodiment provides a compound of Formula (VII), wherein W is—O— and X is alkyl. Another embodiment provides a compound of Formula(VII), wherein W is —O— and X is alkynyl. Another embodiment provides acompound of Formula (VII), wherein W is —O— and X is aryl. Anotherembodiment provides a compound of Formula (VII), wherein W is —O— and Xis cycloalkylalkyl. Another embodiment provides a compound of Formula(VII), wherein W is —O— and X is cycloalkylalkynyl. Another embodimentprovides a compound of Formula (VII), wherein the R⁶ is CD₃.

One embodiment provides a compound of Formula (VIla), or apharmaceutically acceptable salt thereof,

-   -   wherein,    -   R² is CH₃, CH₂CH₃, CH₂CF₃, CH₂F, CHF₂, CF₃, CH₂D, CHD₂, or CD₃;    -   X6 is C—H or N;    -   X5 is C—R⁵ or N; provided that if X6 is N, then X5 is C—R⁵, and        if X5 is N, then X6 is CH;    -   R⁵ is hydrogen, halogen, —OH, —CN, —OR⁶¹, —NHR⁶¹, —N(R⁶¹)₂,        alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,        heterocyclylalkyl, heteroaryl, or heteroarylalkyl, wherein each        R⁶¹ is independently selected from alkyl, cycloalkyl,        cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,        heteroaryl, or heteroarylalkyl;    -   R⁶ is hydrogen, halogen, —OH, —CN, alkyl, alkynyl, cycloalkyl,        cycloalkylalkyl, cycloalkylalkynyl, amino, alkylamino,        dialkylamino, heterocyclyl, cycloalkylalkylamino, alkoxy,        cycloalkyloxy, cycloalkylalkoxy, alkyl-S—, cycloalkyl-S—, and        cycloalkylalkyl-S—;    -   R^(A) is

-   -   X2 is N or C—R¹², wherein R¹² is hydrogen, halogen, alkyl, or        alkoxy;    -   R¹³ is —Y—Z;    -   Y is selected from a bond, —CH₂—, or —CH(C₁-C₄ alkyl)-;    -   Z is selected from —N(R²²)SO₂R²¹, —N(R²²)CO₂R²¹, —N(R²²)COR²¹,        or —N(R²²)SO₃R²¹;    -   X3 is N or C—R¹⁴, wherein R¹⁴ is hydrogen, halogen, —CN, alkyl,        cycloalkyl, or alkoxy; or optionally when X4 is C—R¹⁵, R¹⁴ and        R¹⁵ connect to form a ring;    -   X4 is N or C—R¹⁵, wherein R¹⁵ is hydrogen, halogen, —CN, alkyl,        or alkoxy;    -   R¹⁶ is hydrogen, halogen, or —W—X, wherein W is a bond, —O—,        —S—, or —NH—, and X is selected from alkyl, alkynyl, aryl,        aralkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkynyl,        heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;        or optionally when X4 is C—R¹⁵, R¹⁶ and R¹⁵ connect to form a        ring;    -   each R²¹ is independently selected from alkyl, cycloalkyl,        cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,        heteroaryl, or heteroarylalkyl; or optionally when R²¹ and R²²        are alkyl, R²¹ and R²² connect to form a ring; and    -   each R²² is independently selected from hydrogen, alkyl,        cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,        heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

Another embodiment provides a compound of Formula (VIIa), wherein X2 isN. Another embodiment provides a compound of Formula (VIIa), wherein X3is N. Another embodiment provides a compound of Formula (VIIa), whereinX4 is N. Another embodiment provides a compound of Formula (VIIa),wherein X2 and X3 are N. Another embodiment provides a compound ofFormula (VIIa), wherein X2 is C—R¹², X3 is C—R¹⁴, and X4 is C—R¹⁵.

Another embodiment provides a compound of Formula (VIIa), wherein R² isCH₃. Another embodiment provides a compound of Formula (VIIa), whereinX6 is C—H. Another embodiment provides a compound of Formula (VIIa),wherein X6 is N. Another embodiment provides a compound of Formula(VIIa), wherein X5 is C—R⁵. Another embodiment provides a compound ofFormula (VIIa), wherein X5 is N. Another embodiment provides a compoundof Formula (VIIa), wherein R⁵ is hydrogen, halogen, or alkyl. Anotherembodiment provides a compound of Formula (VIIa, wherein R⁶ is hydrogen,halogen, or alkyl. Another embodiment provides a compound of Formula(VIIa), wherein R⁶ is heterocyclyl. Another embodiment provides acompound of Formula (VIIa), wherein R⁶ is cycloalkylalkynyl. Anotherembodiment provides a compound of Formula (VIIa), wherein R⁶ is alkoxy,cycloalkyloxy, or cycloalkylalkoxy.

Another embodiment provides a compound of Formula (VIIa), wherein Y is abond. Another embodiment provides a compound of Formula (VIIa), whereinY is a —CH₂—. Another embodiment provides a compound of Formula (VIIa),wherein Z is —N(R²²)SO₂R²¹. Another embodiment provides a compound ofFormula (VIIa), wherein Z is —N(R²²)CO₂R²¹. Another embodiment providesa compound of Formula (VIIa), wherein R21 is alkyl, cycloalkyl, orcycloalkylalkyl. Another embodiment provides a compound of Formula(VIIa), wherein R²¹ is alkyl. Another embodiment provides a compound ofFormula (VIIa), wherein R²² is alkyl. Another embodiment provides acompound of Formula (VIIa), wherein both R²¹ and R²² are alkyl andconnect to form a ring. Another embodiment provides a compound ofFormula (VIIa), wherein R¹⁴ is hydrogen, halogen, or alkyl. Anotherembodiment provides a compound of Formula (VIIa), wherein X4 is C—R¹⁵.Another embodiment provides a compound of Formula (VIIa), wherein W is—O—. Another embodiment provides a compound of Formula (VIIa), wherein Wis —NH—. Another embodiment provides a compound of Formula (VIIa),wherein X is alkyl. Another embodiment provides a compound of Formula(VIIa), wherein X is alkynyl. Another embodiment provides a compound ofFormula (VIIa), wherein X is aryl. Another embodiment provides acompound of Formula (VIIa), wherein X is cycloalkylalkyl. Anotherembodiment provides a compound of Formula (VIIa), wherein X iscycloalkylalkynyl. Another embodiment provides a compound of Formula(VIIa), wherein W is —O— and X is alkyl. Another embodiment provides acompound of Formula (VIIa), wherein W is —O— and X is alkynyl. Anotherembodiment provides a compound of Formula (VIIa), wherein W is —O— and Xis aryl. Another embodiment provides a compound of Formula (VIIa),wherein W is —O— and X is cycloalkylalkyl. Another embodiment provides acompound of Formula (VIIa), wherein W is —O— and X is cycloalkylalkynyl.Another embodiment provides a compound of Formula (VIIa), wherein the R⁶is CD₃.

One embodiment provides a compound of Formula (VIII), or apharmaceutically acceptable salt thereof,

-   -   wherein,    -   R² is selected from CH₃, CH₂CH₃, CH₂CF₃, CH₂F, CHF₂, CF₃, CH₂D,        CHD₂, or CD₃;    -   X5 is C—R⁵ or N;    -   X6 is C—R⁶ or N;    -   X7 is C—R⁷ or N;    -   X8 is C—R⁸ or N; wherein no more than two of X5, X6, X7, or X8        may be N;    -   R⁵ is hydrogen, halogen, —OH, —CN, —OR⁶¹, —NHR⁶¹, —N(R⁶¹)₂,        alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,        heterocyclylalkyl, heteroaryl, or heteroarylalkyl, wherein each        R⁶¹ is independently selected from alkyl, cycloalkyl,        cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,        heteroaryl, or heteroarylalkyl;    -   R⁶ is hydrogen, halogen, —OH, —CN, —OR⁶¹, —NHR⁶¹, —N(R⁶¹)₂,        alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,        heterocyclylalkyl, heteroaryl, or heteroarylalkyl, wherein each        R⁶¹ is independently selected from alkyl, cycloalkyl,        cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,        heteroaryl, or heteroarylalkyl;    -   R⁷ is hydrogen, halogen, —OH, —CN, —OR⁶¹, —NHR⁶¹, —N(R⁶¹)₂,        alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,        heterocyclylalkyl, heteroaryl, or heteroarylalkyl, wherein each        R⁶¹ is independently selected from alkyl, cycloalkyl,        cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,        heteroaryl, or heteroarylalkyl;    -   R⁸ is hydrogen, halogen, or alkyl;    -   R^(A) is

-   -   X2 is N or C—R¹², wherein R¹² is hydrogen, halogen, alkyl, or        alkoxy;    -   R¹³ is —Y—Z;    -   Y is selected from a bond, —CH₂—, or —CH(C₁-C₄ alkyl)-;    -   Z is selected from —SO₂R²¹, —N(R²²)SO₂R²¹, —SO₂N(R²²)₂,        —N(R²²)SO₂N(R²²)₂, —CON(R²²)₂, —N(R²²)CO₂R²¹, —N(R²²)CON(R²²)₂,        —N(R²²)COR²¹, —OC(O)N(R²²)₂, —OSO₂N(R²²)₂, or —N(R²²)SO₃R²¹;    -   X3 is N or C—R¹⁴, wherein R¹⁴ is hydrogen, halogen, —CN, alkyl,        cycloalkyl, or alkoxy; or optionally when X4 is C—R¹⁵, R¹⁴ and        R¹⁵ connect to form a ring;    -   X4 is N or C—R¹⁵, wherein R¹⁵ is hydrogen, halogen, —CN, alkyl,        or alkoxy;    -   R¹⁶ is hydrogen, halogen, or —W—X, wherein W is a bond, —O—,        —S—, or —NH—, and X is selected from alkyl, alkynyl, aryl,        aralkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkynyl,        heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;        or optionally when X4 is C—R¹⁵, R¹⁶ and R¹⁵ connect to form a        ring;    -   each R²¹ is independently selected from alkyl, cycloalkyl,        cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,        heteroaryl, or heteroarylalkyl; and    -   each R²² is independently selected from hydrogen, alkyl,        cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,        heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

Another embodiment provides a compound of Formula (VIII), wherein R² isCH₃. Another embodiment provides a compound of Formula (VIII), whereinR² is CD₃. Another embodiment provides a compound of Formula (VIII),wherein X5 is N. Another embodiment provides a compound of Formula(VIII), wherein X6 is N. Another embodiment provides a compound ofFormula (VIII), wherein X7 is N. Another embodiment provides a compoundof Formula (VIII), wherein X8 is N. Another embodiment provides acompound of Formula (VIII), wherein none of X5, X6, X7, or X8 is N.Another embodiment provides a compound of Formula (VIII), wherein R⁵ andR⁸ are hydrogen. Another embodiment provides a compound of Formula(VIII), wherein R⁵, R⁶, R⁷ and R⁸ are hydrogen. Another embodimentprovides a compound of Formula (VIII), wherein R⁷ is a halogen. Anotherembodiment provides a compound of Formula (VIII), wherein R⁶ is ahalogen. Another embodiment provides a compound of Formula (VIII),wherein R⁶ is a heteroaryl. Another embodiment provides a compound ofFormula (VIII), wherein R⁶ is an aryl. Another embodiment provides acompound of Formula (VIII), wherein R⁶ is an alkyl. Another embodimentprovides a compound of Formula (VIII), wherein R⁶ is an aryl.

Another embodiment provides a compound of Formula (VIII), wherein Y is abond. Another embodiment provides a compound of Formula (VIII), whereinY is a —CH₂—. Another embodiment provides a compound of Formula (VIII),wherein Z is —SO₂R²1. Another embodiment provides a compound of Formula(VIII), wherein Z is —N(R²²)SO₂R²¹. Another embodiment provides acompound of Formula (VIII), wherein Z is —SO₂N(R²²)₂. Another embodimentprovides a compound of Formula (VIII), wherein Z is —N(R²²)SO₂N(R²²)₂.Another embodiment provides a compound of Formula (VIII), wherein Z is—CON(R²²)2. Another embodiment provides a compound of Formula (VIII),wherein Z is —N(R²²)CO₂R²¹. Another embodiment provides a compound ofFormula (VIII), wherein Z is —N(R²²)CON(R²²)₂. Another embodimentprovides a compound of Formula (VIII), wherein R²¹ is alkyl, cycloalkyl,or cycloalkylalkyl. Another embodiment provides a compound of Formula(VIII), wherein R21 is alkyl. Another embodiment provides a compound ofFormula (VIII), wherein R¹⁴ is hydrogen, halogen, or alkyl. Anotherembodiment provides a compound of Formula (VIII), wherein X4 is C—R¹⁵.Another embodiment provides a compound of Formula (VIII), wherein W is—O—. Another embodiment provides a compound of Formula (VIII), wherein Wis —NH—. Another embodiment provides a compound of Formula (VIII),wherein X is alkyl. Another embodiment provides a compound of Formula(VIII), wherein X is aryl. Another embodiment provides a compound ofFormula (VIII), wherein X is cycloalkylalkyl. Another embodimentprovides a compound of Formula (VIII), wherein W is —O— and X is alkyl.Another embodiment provides a compound of Formula (VIII), wherein W is—O— and X is aryl. Another embodiment provides a compound of Formula(VIII), wherein W is —O— and X is cycloalkylalkyl. Another embodimentprovides a compound of Formula (VIII), wherein R⁵ and R⁸ are hydrogen.Another embodiment provides a compound of Formula (VIII), wherein R⁵ andR⁸ are hydrogen, and R⁶ is heteroaryl.

One embodiment provides a compound of Formula (VIIIa), or apharmaceutically acceptable salt thereof,

-   -   wherein,    -   R² is selected from CH₃, CH₂CH₃, CH₂CF₃, CH₂F, CHF₂, CF₃, CH₂D,        CHD₂, or CD₃;    -   X5 is C—R⁵ or N;    -   X6 is C—R⁶ or N;    -   X7 is C—R⁷ or N;    -   X8 is C—R⁸ or N; wherein no more than two of X5, X6, X7, or X8        may be N;    -   R⁵ is hydrogen, halogen, —OH, —CN, —OR⁶¹, —NHR⁶¹, —N(R⁶¹)₂,        alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,        heterocyclylalkyl, heteroaryl, or heteroarylalkyl, wherein each        R⁶¹ is independently selected from alkyl, cycloalkyl,        cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,        heteroaryl, or heteroarylalkyl;    -   R⁶ is hydrogen, halogen, —OH, —CN, —OR⁶¹, —NHR⁶¹, —N(R⁶¹)₂,        alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,        heterocyclylalkyl, heteroaryl, or heteroarylalkyl, wherein each        R⁶¹ is independently selected from alkyl, cycloalkyl,        cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,        heteroaryl, or heteroarylalkyl;    -   R⁷ is hydrogen, halogen, —OH, —CN, —OR⁶¹, —NHR⁶¹, —N(R⁶¹)₂,        alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,        heterocyclylalkyl, heteroaryl, or heteroarylalkyl, wherein each        R⁶¹ is independently selected from alkyl, cycloalkyl,        cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,        heteroaryl, or heteroarylalkyl;    -   R⁸ is hydrogen, halogen, or alkyl;    -   R^(A) is

-   -   X2 is N or C—R¹², wherein R¹² is hydrogen, halogen, alkyl, or        alkoxy;    -   R¹³ is —Y—Z;    -   Y is selected from a bond, —CH₂—, or —CH(C₁-C₄ alkyl)-;    -   Z is selected from —N(R²²)SO₂R²¹, —N(R²²)CO₂R²¹, —N(R²²)COR²¹,        or —N(R²²)SO₃R²¹; X3 is N or C—R¹⁴, wherein R¹⁴ is hydrogen,        halogen, —CN, alkyl, cycloalkyl, or alkoxy; or optionally when        X4 is C—R¹⁵, R¹⁴ and R¹⁵ connect to form a ring;    -   X4 is N or C—R¹⁵, wherein R¹⁵ is hydrogen, halogen, —CN, alkyl,        or alkoxy;    -   R¹⁶ is hydrogen, halogen, or —W—X, wherein W is a bond, —O—,        —S—, or —NH—, and X is selected from alkyl, alkynyl, aryl,        aralkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkynyl,        heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;        or optionally when X4 is C—R¹⁵, R¹⁶ and R¹⁵ connect to form a        ring;    -   each R²¹ is independently selected from alkyl, cycloalkyl,        cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,        heteroaryl, or heteroarylalkyl; or optionally when R²¹ and R²²        are alkyl, R²¹ and R²² connect to form a ring; and    -   each R²² is independently selected from hydrogen, alkyl,        cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,        heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

Another embodiment provides a compound of Formula (VIIIa), wherein R² isCH₃. Another embodiment provides a compound of Formula (VIIIa), whereinR² is CD₃. Another embodiment provides a compound of Formula (VIIIa),wherein X5 is N. Another embodiment provides a compound of Formula(VIIIa), wherein X6 is N. Another embodiment provides a compound ofFormula (VIIIa), wherein X7 is N. Another embodiment provides a compoundof Formula (VIIIa), wherein X8 is N. Another embodiment provides acompound of Formula (VIIIa), wherein none of X5, X6, X7, or X8 is N.Another embodiment provides a compound of Formula (VIIIa), wherein R⁵and R⁸ are hydrogen. Another embodiment provides a compound of Formula(VIIIa), wherein R⁵, R⁶, R⁷ and R⁸ are hydrogen. Another embodimentprovides a compound of Formula (VIIIa), wherein R⁷ is a halogen. Anotherembodiment provides a compound of Formula (VIIIa), wherein R⁶ is ahalogen. Another embodiment provides a compound of Formula (VIIIa),wherein R⁶ is a heteroaryl. Another embodiment provides a compound ofFormula (VIIIa), wherein R⁶ is an aryl. Another embodiment provides acompound of Formula (VIIIa), wherein R⁶ is an alkyl. Another embodimentprovides a compound of Formula (VIIIa), wherein R⁶ is an aryl.

Another embodiment provides a compound of Formula (VIIIa), wherein Y isa bond. Another embodiment provides a compound of Formula (VIIIa),wherein Y is a —CH₂—. Another embodiment provides a compound of Formula(VIIIa), wherein Z is —N(R²²)SO₂R²¹. Another embodiment provides acompound of Formula (VIIIa), wherein Z is —N(R²²)CO₂R²¹. Anotherembodiment provides a compound of Formula (VIIIa), wherein R²¹ is alkyl,cycloalkyl, or cycloalkylalkyl. Another embodiment provides a compoundof Formula (VIIIa), wherein R²¹ is alkyl. Another embodiment provides acompound of Formula (VIIIa), wherein R²² is alkyl. Another embodimentprovides a compound of Formula (VIIIa), wherein both R²¹ and R²² arealkyl and connect to form a ring. Another embodiment provides a compoundof Formula (VIIIa), wherein R¹⁴ is hydrogen, halogen, or alkyl. Anotherembodiment provides a compound of Formula (VIIIa), wherein X4 is C—R¹⁵.Another embodiment provides a compound of Formula (VIIIa), wherein W is—O—. Another embodiment provides a compound of Formula (VIIIa), whereinW is —NH—. Another embodiment provides a compound of Formula (VIIIa),wherein X is alkyl. Another embodiment provides a compound of Formula(VIIIa), wherein X is aryl. Another embodiment provides a compound ofFormula (VIIIa), wherein X is cycloalkylalkyl. Another embodimentprovides a compound of Formula (VIIIa), wherein W is —O— and X is alkyl.Another embodiment provides a compound of Formula (VIIIa), wherein W is—O— and X is aryl. Another embodiment provides a compound of Formula(VIIIa), wherein W is —O— and X is cycloalkylalkyl. Another embodimentprovides a compound of Formula (VIIIa), wherein R⁵ and R⁸ are hydrogen.Another embodiment provides a compound of Formula (VIIIa), wherein R⁵and R⁸ are hydrogen, and R⁶ is heteroaryl.

One embodiment provides a compound of Formula (IX), or apharmaceutically acceptable salt thereof,

-   -   wherein,    -   Q is N and T is C, or Q is C and T is N;    -   Ring B is an optionally substituted 5-membered aromatic        nitrogen-containing heteroaryl ring containing one or more        nitrogen atoms;    -   R² is selected from CH₃, CH₂CH₃, CH₂CF₃, CH₂F, CHF₂, CF₃, CH₂D,        CHD₂, or CD₃;    -   X1 is C—H or N;    -   R^(A) is

-   -   X2 is N or C—R¹², wherein R¹² is hydrogen, halogen, alkyl, or        alkoxy;    -   R¹³ is —Y—Z;    -   Y is selected from a bond, —CH₂—, or —CH(C₁-C₄ alkyl)-;    -   Z is selected from —SO₂R²¹, —N(R²²)SO₂R²¹, —SO₂N(R²²)₂,        —N(R²²)SO₂N(R²²)₂, —CON(R²²)₂, —N(R²²)CO₂R²¹, —N(R²²)CON(R²²)₂,        —N(R²²)COR²¹, —OC(O)N(R²²)₂, —OSO₂N(R²²)₂, or —N(R²²)SO₃R²¹;    -   X3 is N or C—R¹⁴, wherein R¹⁴ is hydrogen, halogen, —CN, alkyl,        cycloalkyl, or alkoxy; or optionally when X4 is C—R¹⁵, R¹⁴ and        R¹⁵ connect to form a ring;    -   X4 is N or C—R¹⁵, wherein R¹⁵ is hydrogen, halogen, —CN, alkyl,        or alkoxy;    -   R¹⁶ is hydrogen, halogen, or —W—X, wherein W is a bond, —O—,        —S—, or —NH—, and X is selected from alkyl, alkynyl, aryl,        aralkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkynyl,        heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;        or optionally when X4 is C—R¹⁵, R¹⁶ and R¹⁵ connect to form a        ring;    -   each R²¹ is independently selected from alkyl, cycloalkyl,        cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,        heteroaryl, or heteroarylalkyl; and    -   each R²² is independently selected from hydrogen, alkyl,        cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,        heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

Another embodiment provides a compound of Formula (IX), wherein X2 is N.Another embodiment provides a compound of Formula (IX), wherein X3 is N.Another embodiment provides a compound of Formula (IX), wherein X4 is N.Another embodiment provides a compound of Formula (IX), wherein X2 andX3 are N. Another embodiment provides a compound of Formula (IX),wherein X2 is C—R¹², X3 is C—R¹⁴, and X4 is C—R¹⁵.

Another embodiment provides a compound of Formula (IX), wherein thecompound of Formula (IX) is selected from the group:

Another embodiment provides a compound of Formula (IX), wherein Q is Nand T is C. Another embodiment provides a compound of Formula (IX),wherein Q is C and T is N. Another embodiment provides a compound ofFormula (IX), wherein R² is CH₃. Another embodiment provides a compoundof Formula (IX), wherein X1 is C—H. Another embodiment provides acompound of Formula (IX), wherein X1 is N.

Another embodiment provides a compound of Formula (IX), wherein Y is abond. Another embodiment provides a compound of Formula (IX), wherein Yis a —CH₂—. Another embodiment provides a compound of Formula (IX),wherein Z is —SO₂R²¹. Another embodiment provides a compound of Formula(IX), wherein Z is —N(R²²)SO₂R²¹. Another embodiment provides a compoundof Formula (IX), wherein Z is —SO₂N(R²²)₂. Another embodiment provides acompound of Formula (IX), wherein Z is —N(R²²)SO₂N(R²²)₂. Anotherembodiment provides a compound of Formula (IX), wherein Z is —CON(R²²)₂.Another embodiment provides a compound of Formula (IX), wherein Z is—N(R²²)CO₂R²¹. Another embodiment provides a compound of Formula (IX),wherein Z is —N(R²²)CON(R²²)₂. Another embodiment provides a compound ofFormula (IX), wherein R²¹ is alkyl, cycloalkyl, or cycloalkylalkyl.Another embodiment provides a compound of Formula (IX), wherein R²¹ isalkyl.

Another embodiment provides a compound of Formula (IX), wherein R14 ishydrogen, halogen, or alkyl. Another embodiment provides a compound ofFormula (IX), wherein X4 is C—R¹⁵. Another embodiment provides acompound of Formula (IX), wherein W is —O—. Another embodiment providesa compound of Formula (IX), wherein W is —NH—. Another embodimentprovides a compound of Formula (IX), wherein X is alkyl. Anotherembodiment provides a compound of Formula (IX), wherein X is aryl.Another embodiment provides a compound of Formula (IX), wherein X iscycloalkylalkyl. Another embodiment provides a compound of Formula (IX),wherein W is —O— and X is alkyl. Another embodiment provides a compoundof Formula (IX), wherein W is —O— and X is aryl. Another embodimentprovides a compound of Formula (IX), wherein W is —O— and X iscycloalkylalkyl.

One embodiment provides a compound of Formula (XII), or apharmaceutically acceptable salt thereof,

-   -   wherein,    -   R² is selected from CH₃, CH₂CH₃, CH₂CF₃, CH₂F, CHF₂, CF₃, CH₂D,        CHD₂, or CD₃;    -   X5 is C—R⁵ or N;    -   X6 is C—R⁶ or N;    -   X7 is C—R⁷ or N;    -   X8 is C—R⁸ or N; wherein no more than two of X5, X6, X7, or X8        may be N;    -   R⁵ is hydrogen, halogen, —OH, —CN, —OR⁶¹, —NHR⁶¹, —N(R⁶¹)₂,        alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,        heterocyclylalkyl, heteroaryl, or heteroarylalkyl, wherein each        R⁶¹ is independently selected from alkyl, cycloalkyl,        cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,        heteroaryl, or heteroarylalkyl;    -   R⁶ is hydrogen, halogen, —OH, —CN, —OR⁶¹, —NHR⁶¹, —N(R⁶¹)₂,        alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,        heterocyclylalkyl, heteroaryl, or heteroarylalkyl, wherein each        R⁶¹ is independently selected from alkyl, cycloalkyl,        cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,        heteroaryl, or heteroarylalkyl;    -   R⁷ is hydrogen, halogen, —OH, —CN, —OR⁶¹, —NHR⁶¹, —N(R⁶¹)₂,        alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,        heterocyclylalkyl, heteroaryl, or heteroarylalkyl, wherein each        R⁶¹ is independently selected from alkyl, cycloalkyl,        cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,        heteroaryl, or heteroarylalkyl;    -   R⁸ is hydrogen, halogen, or alkyl;    -   R^(A) is

-   -   X2 is N or C—R¹², wherein R¹² is hydrogen, halogen, alkyl, or        alkoxy;    -   R¹³ is —Y—Z;    -   Y is selected from a bond, —CH₂—, or —CH(C₁-C₄ alkyl)-;    -   Z is selected from —SO₂R²¹, —N(R²²)SO₂R²¹, —SO₂N(R²²)₂,        —N(R²²)SO₂N(R²²)₂, —CON(R²²)₂, —N(R²²)CO₂R²¹, —N(R²²)CON(R²²)₂,        —N(R²²)COR²¹, —OC(O)N(R²²)₂, —OSO₂N(R²²)₂, or —N(R²²)SO₃R²¹;    -   X3 is S;    -   X4 is N or C—R¹⁴, wherein R¹⁴ is hydrogen, halogen, alkyl, or        alkoxy;    -   R¹⁶ is hydrogen, halogen, or —W—X, wherein W is a bond, —O—,        —S—, or —NH—, and X is selected from alkyl, alkynyl, aryl,        aralkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkynyl,        heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;    -   each R²¹ is independently selected from alkyl, cycloalkyl,        cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,        heteroaryl, or heteroarylalkyl; and    -   each R²² is independently selected from hydrogen, alkyl,        cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,        heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

Another embodiment provides a compound of Formula (XII), wherein R² isCH₃. Another embodiment provides a compound of Formula (XII), wherein R²is CD₃. Another embodiment provides a compound of Formula (XII), whereinX5 is N. Another embodiment provides a compound of Formula (XII),wherein X6 is N. Another embodiment provides a compound of Formula(XII), wherein X7 is N. Another embodiment provides a compound ofFormula (XII), wherein X8 is N. Another embodiment provides a compoundof Formula (XII), wherein none of X5, X6, X7, or X8 is N. Anotherembodiment provides a compound of Formula (XII), wherein R⁵ and R⁸ arehydrogen. Another embodiment provides a compound of Formula (XII),wherein R⁵, R⁶, R⁷, and R⁸ are hydrogen. Another embodiment provides acompound of Formula (XII), wherein R⁷ is a halogen. Another embodimentprovides a compound of Formula (XII), wherein R⁶ is a halogen. Anotherembodiment provides a compound of Formula (XII), wherein R⁶ is aheteroaryl. Another embodiment provides a compound of Formula (XII),wherein R⁶ is an aryl. Another embodiment provides a compound of Formula(XII), wherein R⁶ is an alkyl. Another embodiment provides a compound ofFormula (XII), wherein R⁶ is an aryl.

Another embodiment provides a compound of Formula (XII), wherein Y is abond. Another embodiment provides a compound of Formula (XII), wherein Yis a —CH₂—. Another embodiment provides a compound of Formula (XII),wherein Z is —SO₂R²¹. Another embodiment provides a compound of Formula(XII), wherein Z is —N(R²²)SO₂R²¹. Another embodiment provides acompound of Formula (XII), wherein Z is —SO₂N(R²²)₂. Another embodimentprovides a compound of Formula (XII), wherein Z is —N(R²²)SO₂N(R²²)₂.Another embodiment provides a compound of Formula (XII), wherein Z is—CON(R²²)₂. Another embodiment provides a compound of Formula (XII),wherein Z is —N(R²²)CO₂R²¹. Another embodiment provides a compound ofFormula (XII), wherein Z is —N(R²²)CON(R²²)₂. Another embodimentprovides a compound of Formula (XII), wherein R²¹ is alkyl, cycloalkyl,or cycloalkylalkyl. Another embodiment provides a compound of Formula(XII), wherein R²¹ is alkyl. Another embodiment provides a compound ofFormula (XII), wherein W is —O—. Another embodiment provides a compoundof Formula (XII), wherein W is —NH—. Another embodiment provides acompound of Formula (XII), wherein X is alkyl. Another embodimentprovides a compound of Formula (XII), wherein X is aryl. Anotherembodiment provides a compound of Formula (XII), wherein X iscycloalkylalkyl. Another embodiment provides a compound of Formula(XII), wherein W is —O— and X is alkyl. Another embodiment provides acompound of Formula (XII), wherein W is —O— and X is aryl. Anotherembodiment provides a compound of Formula (XII), wherein W is —O— and Xis cycloalkylalkyl. Another embodiment provides a compound of Formula(XII), wherein R⁵ and R⁸ are hydrogen. Another embodiment provides acompound of Formula (XII), wherein R⁵ and R⁸ are hydrogen, and R⁶ isheteroaryl.

Another embodiment provides a compound of Formula (XII), wherein

R^(A) is

Another embodiment provides a compound of Formula (XII), wherein R^(A)is

and X2 is N.

Another embodiment provides a compound of Formula (XII), wherein R^(A)is

and X2 is C—R¹².

Another embodiment provides a compound of Formula (XII), wherein R^(A)is

Another embodiment provides a compound of Formula (XII), wherein R^(A)is

and X4 is N.

Another embodiment provides a compound of Formula (XII), wherein R^(A)is

and X4 is C—R¹⁴.

One embodiment provides a compound of Formula (XIII), or apharmaceutically acceptable salt thereof,

-   -   wherein,    -   R² is selected from CH₃, CH₂CH₃, CH₂CF₃, CH₂F, CHF₂, CF₃, CH₂D,        CHD₂, or CD₃;    -   X5 is C—R⁵ or N;    -   X6 is C—R⁶ or N;    -   X7 is C—R⁷ or N;    -   X8 is C—R⁸ or N; wherein no more than two of X5, X6, X7, or X8        may be N;    -   R⁵ is hydrogen, halogen, —OH, —CN, —OR⁶¹, —NHR⁶¹, —N(R⁶¹)₂,        alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,        heterocyclylalkyl, heteroaryl, or heteroarylalkyl, wherein each        R⁶¹ is independently selected from alkyl, cycloalkyl,        cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,        heteroaryl, or heteroarylalkyl;    -   R⁶ is hydrogen, halogen, —OH, —CN, —OR⁶¹, —NHR⁶¹, —N(R⁶¹)₂,        alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,        heterocyclylalkyl, heteroaryl, or heteroarylalkyl, wherein each        R⁶¹ is independently selected from alkyl, cycloalkyl,        cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,        heteroaryl, or heteroarylalkyl;    -   R⁷ is hydrogen, halogen, —OH, —CN, —OR⁶¹, —NHR⁶¹, —N(R⁶¹)₂,        alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,        heterocyclylalkyl, heteroaryl, or heteroarylalkyl, wherein each        R⁶¹ is independently selected from alkyl, cycloalkyl,        cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,        heteroaryl, or heteroarylalkyl;    -   R⁸ is hydrogen, halogen, or alkyl;    -   R^(A) is

-   -   -   R¹² is hydrogen or C₁-C₄ alkyl;        -   R¹³ is —Y—Z;        -   Y is selected from —CH₂—, or —CH(C₁-C₄ alkyl)-;        -   Z is selected from —SO₂R²¹, —SO₂N(R²²)₂, or —CON(R²²)₂;        -   R¹⁵ is hydrogen, halogen or C₁-C₄ alkyl;        -   R¹⁶ is hydrogen, halogen, or —W—X, wherein W is a bond, —O—,            —S—, or —NH—, and X is selected from alkyl, alkynyl, aryl,            aralkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkynyl,            heterocyclyl, heterocyclylalkyl, heteroaryl, or            heteroarylalkyl; or optionally, R¹⁶ and R¹⁵ connect to form            a ring;        -   each R²¹ is independently selected from alkyl, cycloalkyl,            cycloalkylalkyl, aryl, aralkyl, heterocyclyl,            heterocyclylalkyl, heteroaryl, or heteroarylalkyl; and        -   each R²² is independently selected from hydrogen, alkyl,            cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,            heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

Another embodiment provides a compound of Formula (XIII), wherein R² isCH₃. Another embodiment provides a compound of Formula (XIII), whereinR² is CD₃. Another embodiment provides a compound of Formula (XIII),wherein X5 is N. Another embodiment provides a compound of Formula(XIII), wherein X6 is N. Another embodiment provides a compound ofFormula (XIII), wherein X7 is N. Another embodiment provides a compoundof Formula (XIII), wherein X8 is N. Another embodiment provides acompound of Formula (XIII), wherein none of X5, X6, X7, or X8 is N.Another embodiment provides a compound of Formula (XIII), wherein R⁵ andR⁸ are hydrogen. Another embodiment provides a compound of Formula(XIII), wherein R⁵, R⁶, R⁷, and R⁸ are hydrogen. Another embodimentprovides a compound of Formula (XIII), wherein R⁷ is a halogen. Anotherembodiment provides a compound of Formula (XIII), wherein R⁶ is ahalogen. Another embodiment provides a compound of Formula (XIII),wherein R⁶ is a heteroaryl. Another embodiment provides a compound ofFormula (XIII), wherein R⁶ is an aryl. Another embodiment provides acompound of Formula (XIII), wherein R⁶ is an alkyl. Another embodimentprovides a compound of Formula (XIII), wherein R⁶ is an aryl.

Another embodiment provides a compound of Formula (XIII), wherein Y is a—CH₂—. Another embodiment provides a compound of Formula (XIII), whereinZ is —SO₂R²¹. Another embodiment provides a compound of Formula (XIII),wherein Z is —SO₂N(R²²)₂. Another embodiment provides a compound ofFormula (XIII), wherein Z is —CON(R²²)₂. Another embodiment provides acompound of Formula (XIII), wherein R²¹ is alkyl, cycloalkyl, orcycloalkylalkyl. Another embodiment provides a compound of Formula(XIII), wherein R²¹ is alkyl. Another embodiment provides a compound ofFormula (XIII), wherein W is —O—. Another embodiment provides a compoundof Formula (XIII), wherein W is —NH—. Another embodiment provides acompound of Formula (XIII), wherein X is alkyl. Another embodimentprovides a compound of Formula (XIII), wherein X is aryl. Anotherembodiment provides a compound of Formula (XIII), wherein X iscycloalkylalkyl. Another embodiment provides a compound of Formula(XIII), wherein W is —O— and X is alkyl. Another embodiment provides acompound of Formula (XIII), wherein W is —O— and X is aryl. Anotherembodiment provides a compound of Formula (XIII), wherein W is —O— and Xis cycloalkylalkyl. Another embodiment provides a compound of Formula(XIII), wherein R⁵ and R⁸ are hydrogen. Another embodiment provides acompound of Formula (XIII), wherein R⁵ and R⁸ are hydrogen, and R⁶ isheteroaryl.

One embodiment provides a compound of Formula (XIV), or apharmaceutically acceptable salt thereof,

-   -   wherein,    -   R² is CH₃, CH₂CH₃, CH₂CF₃, CH₂F, CHF₂, CF₃, CH₂D, CHD₂, or CD₃;    -   X6 is C—H or N;    -   X5 is C—R⁵ or N; provided that if X6 is N, then X5 is C—R⁵, and        if X5 is N, then X6 is CH;    -   R⁵ is hydrogen, halogen, —OH, —CN, —OR⁶¹, —NHR⁶¹, —N(R⁶¹)₂,        alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,        heterocyclylalkyl, heteroaryl, or heteroarylalkyl, wherein each        R⁶¹ is independently selected from alkyl, cycloalkyl,        cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,        heteroaryl, or heteroarylalkyl;    -   R⁶ is hydrogen, halogen, —OH, —CN, alkyl, alkynyl, cycloalkyl,        cycloalkylalkyl, cycloalkylalkynyl, amino, alkylamino,        dialkylamino, heterocyclyl, cycloalkylalkylamino, alkoxy,        cycloalkyloxy, cycloalkylalkoxy, alkyl-S—, cycloalkyl-S—, and        cycloalkylalkyl-S—;    -   R^(A) is

-   -   R¹² is hydrogen or C₁-C₄ alkyl;    -   R¹³ is —Y—Z;    -   Y is selected from —CH₂—, or —CH(C₁-C₄ alkyl)-;    -   Z is selected from —SO₂R²¹, —SO₂N(R²²)₂, or —CON(R²²)₂;    -   R¹⁵ is hydrogen, halogen or C₁-C₄ alkyl;    -   R¹⁶ is hydrogen, halogen, or —W—X, wherein W is a bond, —O—,        —S—, or —NH—, and X is selected from alkyl, alkynyl, aryl,        aralkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkynyl,        heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;        or optionally, R¹⁶ and R¹⁵ connect to form a ring;    -   each R²¹ is independently selected from alkyl, cycloalkyl,        cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,        heteroaryl, or heteroarylalkyl; and    -   each R²² is independently selected from hydrogen, alkyl,        cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,        heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

Another embodiment provides a compound of Formula (XIV), wherein R² isCH₃. Another embodiment provides a compound of Formula (XIV), wherein X6is C—H. Another embodiment provides a compound of Formula (XIV), whereinX6 is N. Another embodiment provides a compound of Formula (XIV),wherein X5 is C—R⁵. Another embodiment provides a compound of Formula(XIV), wherein X5 is N. Another embodiment provides a compound ofFormula (XIV), wherein R⁵ is hydrogen, halogen, or alkyl. Anotherembodiment provides a compound of Formula (XIV), wherein R⁶ is hydrogen,halogen, or alkyl. Another embodiment provides a compound of Formula(XIV), wherein R⁶ is heterocyclyl. Another embodiment provides acompound of Formula (XIV), wherein R⁶ is cycloalkylalkynyl. Anotherembodiment provides a compound of Formula (XIV), wherein R⁶ is alkoxy,cycloalkyloxy, or cycloalkylalkoxy.

Another embodiment provides a compound of Formula (XIV), wherein Y is a—CH₂—. Another embodiment provides a compound of Formula (XIV), whereinZ is —SO₂R²¹. Another embodiment provides a compound of Formula (XIV),wherein Z is —SO₂N(R²²)₂. Another embodiment provides a compound ofFormula (XIV), wherein Z is —CON(R²²)₂. Another embodiment provides acompound of Formula (XIV), wherein R²¹ is alkyl, cycloalkyl, orcycloalkylalkyl. Another embodiment provides a compound of Formula(XIV), wherein R²¹ is alkyl. Another embodiment provides a compound ofFormula (XIV), wherein W is —O—. Another embodiment provides a compoundof Formula (XIV), wherein W is —NH—. Another embodiment provides acompound of Formula (XIV), wherein X is alkyl. Another embodimentprovides a compound of Formula (XIV), wherein X is alkynyl. Anotherembodiment provides a compound of Formula (XIV), wherein X is aryl.Another embodiment provides a compound of Formula (XIV), wherein X iscycloalkylalkyl. Another embodiment provides a compound of Formula(XIV), wherein X is cycloalkylalkynyl. Another embodiment provides acompound of Formula (XIV), wherein W is —O— and X is alkyl. Anotherembodiment provides a compound of Formula (XIV), wherein W is —O— and Xis alkynyl. Another embodiment provides a compound of Formula (XIV),wherein W is —O— and X is aryl. Another embodiment provides a compoundof Formula (XIV), wherein W is —O— and X is cycloalkylalkyl. Anotherembodiment provides a compound of Formula (XIV), wherein W is —O— and Xis cycloalkylalkynyl. Another embodiment provides a compound of Formula(XIV), wherein the R⁶ is CD₃.

One embodiment provides a compound of Formula (XV), or apharmaceutically acceptable salt thereof,

wherein,

-   -   Ring B is an optionally substituted 5-membered heteroaryl ring        containing at least one oxygen or sulfur atom;    -   R² is selected from CH₃, CH₂CH₃, CH₂CF₃, CH₂F, CHF₂, CF₃, CH₂D,        CHD₂, or CD₃;    -   X1 is C—H or N;    -   R^(A) is

-   -   X2 is N or C—R¹², wherein R¹² is hydrogen, halogen, alkyl, or        alkoxy;    -   R¹³ is —Y—Z;    -   Y is selected from a bond, —CH₂—, or —CH(C₁-C₄ alkyl)-;    -   Z is selected from vSO₂R²¹, —N(R²²)SO₂R²¹, —SO₂N(R²²)₂,        —N(R²²)SO₂N(R²²)₂, —CON(R²²)₂, —N(R²²)CO₂R²¹, —N(R²²)CON(R²²)₂,        —N(R²²)COR²¹, —OC(O)N(R²²)₂, —OSO₂N(R²²)₂, or —N(R²²)SO₃R²¹;    -   X3 is N or C—R¹⁴, wherein R¹⁴ is hydrogen, halogen, —CN, alkyl,        cycloalkyl, or alkoxy; or optionally when X4 is C—R¹⁵, R¹⁴ and        R¹⁵ connect to form a ring;    -   X4 is N or C—R¹⁵, wherein R¹⁵ is hydrogen, halogen, —CN, alkyl,        or alkoxy;    -   R¹⁶ is hydrogen, halogen, or —W—X, wherein W is a bond, —O—,        —S—, or —NH—, and X is selected from alkyl, alkynyl, aryl,        aralkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkynyl,        heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;        or optionally when X4 is C—R¹⁵, R¹⁶ and R¹⁵ connect to form a        ring;    -   each R²¹ is independently selected from alkyl, cycloalkyl,        cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,        heteroaryl, or heteroarylalkyl; and    -   each R²² is independently selected from hydrogen, alkyl,        cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,        heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

Another embodiment provides a compound of Formula (XV), wherein X2 is N.Another embodiment provides a compound of Formula (XV), wherein X3 is N.Another embodiment provides a compound of Formula (XV), wherein X4 is N.Another embodiment provides a compound of Formula (XV), wherein X2 andX3 are N. Another embodiment provides a compound of Formula (XV),wherein X2 is C—R¹², X3 is C—R¹⁴, and X4 is C—R¹⁵.

Another embodiment provides a compound of Formula (XV), wherein thecompound of Formula (XV) has a formula selected from:

-   -   wherein each R³⁰ is independently selected from hydrogen,        halogen, —CN, C₁-C₄ alkyl, —OH, —OR³¹, —NHR³¹, —N(R³¹)₂,        —CONHR³¹, or —CON(R³¹)₂; and R³¹ is C₁-C₄ alkyl.

Another embodiment provides a compound of Formula (XV), wherein thecompound of Formula (XV) has a formula selected from:

-   -   wherein each R³⁰ is independently selected from hydrogen,        halogen, —CN, C₁-C₄ alkyl, —OH, —OR³¹, —NHR³¹, —N(R³¹)₂,        —CONHR³¹, or —CON(R³¹)₂; and R³¹ is C₁-C₄ alkyl.

Another embodiment provides a compound of Formula (XV), wherein thecompound of Formula (XV) has a formula selected from:

-   -   wherein each R³⁰ is independently selected from hydrogen,        halogen, —CN, C₁-C₄ alkyl, —OH, —OR³¹, —NHR³¹, —N(R³¹)₂,        —CONHR³¹, or —CON(R³¹)₂; and R³¹ is C₁-C₄ alkyl.

Another embodiment provides a compound of Formula (XV), wherein R² isCH₃. Another embodiment provides a compound of Formula (XV), wherein X1is C—H. Another embodiment provides a compound of Formula (XV), whereinX1 is N.

Another embodiment provides a compound of Formula (XV), wherein Y is abond. Another embodiment provides a compound of Formula (XV), wherein Yis a —CH₂—. Another embodiment provides a compound of Formula (XV),wherein Z is —SO₂R²¹. Another embodiment provides a compound of Formula(XV), wherein Z is —N(R²²)SO₂R²¹. Another embodiment provides a compoundof Formula (XV), wherein Z is —SO₂N(R²²)₂. Another embodiment provides acompound of Formula (XV), wherein Z is —N(R²²)SO₂N(R²²)₂. Anotherembodiment provides a compound of Formula (XV), wherein Z is —CON(R²²)₂.Another embodiment provides a compound of Formula (XV), wherein Z is—N(R²²)CO₂R²¹. Another embodiment provides a compound of Formula (XV),wherein Z is —N(R²²)CON(R²²)₂. Another embodiment provides a compound ofFormula (XV), wherein R²¹ is alkyl, cycloalkyl, or cycloalkylalkyl.Another embodiment provides a compound of Formula (XV), wherein R²¹ isalkyl.

Another embodiment provides a compound of Formula (XV), wherein X3 isC—R¹⁴. Another embodiment provides a compound of Formula (XV), whereinR¹⁴ is hydrogen, halogen, or alkyl. Another embodiment provides acompound of Formula (XV), wherein X4 is C—R¹⁵. Another embodimentprovides a compound of Formula (XV), wherein W is —O—. Anotherembodiment provides a compound of Formula (XV), wherein W is —NH—.Another embodiment provides a compound of Formula (XV), wherein X isalkyl. Another embodiment provides a compound of Formula (XV), wherein Xis alkynyl. Another embodiment provides a compound of Formula (XV),wherein X is aryl. Another embodiment provides a compound of Formula(XV), wherein X is cycloalkylalkyl. Another embodiment provides acompound of Formula (XV), wherein X is cycloalkylalkynyl. Anotherembodiment provides a compound of Formula (XV), wherein W is —O— and Xis alkyl. Another embodiment provides a compound of Formula (XV),wherein W is —O— and X is aryl. Another embodiment provides a compoundof Formula (XV), wherein W is —O— and X is alkynyl. Another embodimentprovides a compound of Formula (XV), wherein W is —O— and X iscycloalkylalkyl. Another embodiment provides a compound of Formula (XV),wherein W is —O— and X is cycloalkylalkynyl.

Another embodiment provides a compound of Formula (XVI), or apharmaceutically acceptable salt thereof,

-   -   wherein,    -   R² is selected from CH₃, CH₂CH₃, CH₂CF₃, CH₂F, CHF₂, CF₃, CH₂D,        CHD₂, or CD₃;    -   X5 is C—R⁵ or N;    -   X6 is C—R⁶ or N;    -   X7 is C—R⁷ or N;    -   X8 is C—R⁸ or N; wherein no more than two of X5, X6, X7, or X8        may be N;    -   R⁵ is hydrogen, halogen, —OH, —CN, —OR⁶¹, —NHR⁶¹, —N(R⁶¹)₂,        alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,        heterocyclylalkyl, heteroaryl, or heteroarylalkyl, wherein each        R⁶¹ is independently selected from alkyl, cycloalkyl,        cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,        heteroaryl, or heteroarylalkyl;    -   R⁶ is hydrogen, halogen, —OH, —CN, —OR⁶¹, —NHR⁶¹, —N(R⁶¹)₂,        alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,        heterocyclylalkyl, heteroaryl, or heteroarylalkyl, wherein each        R⁶¹ is independently selected from alkyl, cycloalkyl,        cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,        heteroaryl, or heteroarylalkyl;    -   R⁷ is hydrogen, halogen, —OH, —CN, —OR⁶¹, —NHR⁶¹, —N(R⁶¹)₂,        alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,        heterocyclylalkyl, heteroaryl, or heteroarylalkyl, wherein each        R⁶¹ is independently selected from alkyl, cycloalkyl,        cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,        heteroaryl, or heteroarylalkyl;    -   R⁸ is hydrogen, halogen, or alkyl;    -   R^(A) is

-   -   X2 is N or C—R¹², wherein R¹² is hydrogen, halogen, alkyl, or        alkoxy;    -   R¹³ is —Y—Z;    -   Y is selected from a bond, —CH₂—, or —CH(C₁-C₄ alkyl)-;    -   Z is selected from —SO₂R²¹, —N(R²²)SO₂R²¹, —SO₂N(R²²)₂,        —N(R²²)SO₂N(R²²)₂, —CON(R²²)₂, —N(R²²)CO₂R²¹, —N(R²²)CON(R²²)₂,        —N(R²²)COR²¹, —OC(O)N(R²²)₂, —OSO₂N(R²²)₂, or —N(R²²)SO₃R²¹;    -   X3 is N or C—R¹⁴, wherein R¹⁴ is hydrogen, halogen, —CN, alkyl,        cycloalkyl, or alkoxy; or optionally when X4 is C—R¹⁵, R¹⁴ and        R¹⁵ connect to form a ring;    -   X4 is N or C—R¹⁵, wherein R¹⁵ is hydrogen, halogen, —CN, alkyl,        or alkoxy;    -   R¹⁶ is hydrogen, halogen, or —W—X, wherein W is a bond, —O—,        —S—, or —NH—, and X is selected from alkyl, alkynyl, aryl,        aralkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkynyl,        heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;        or optionally when X4 is C—R¹⁵, R¹⁶ and R¹⁵ connect to form a        ring;    -   each R²¹ is independently selected from alkyl, cycloalkyl,        cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,        heteroaryl, or heteroarylalkyl; and    -   each R²² is independently selected from hydrogen, alkyl,        cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,        heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

Another embodiment provides a compound of Formula (XVI), wherein X2 isN. Another embodiment provides a compound of Formula (XVI), wherein X3is N. Another embodiment provides a compound of Formula (XVI), whereinX4 is N. Another embodiment provides a compound of Formula (XVI),wherein X2 and X3 are N. Another embodiment provides a compound ofFormula (XVI), wherein X2 is C—R¹², X3 is C—R¹⁴, and X4 is C—R¹⁵.

Another embodiment provides a compound of Formula (XVI), wherein R² isCH₃. Another embodiment provides a compound of Formula (XVI), wherein R²is CD₃. Another embodiment provides a compound of Formula (XVI), whereinX5 is N. Another embodiment provides a compound of Formula (XVI),wherein X6 is N. Another embodiment provides a compound of Formula(XVI), wherein X7 is N. Another embodiment provides a compound ofFormula (XVI), wherein X8 is N. Another embodiment provides a compoundof Formula (XVI), wherein none of X5, X6, X7, or X8 is N. Anotherembodiment provides a compound of Formula (XVI), wherein R⁵ and R⁸ arehydrogen. Another embodiment provides a compound of Formula (XVI),wherein R⁵, R⁶, R⁷, and R⁸ are hydrogen. Another embodiment provides acompound of Formula (XVI), wherein R⁷ is a halogen. Another embodimentprovides a compound of Formula (XVI), wherein R⁶ is a halogen. Anotherembodiment provides a compound of Formula (XVI), wherein R⁶ is aheteroaryl. Another embodiment provides a compound of Formula (XVI),wherein R⁶ is an aryl. Another embodiment provides a compound of Formula(XVI), wherein R⁶ is an alkyl. Another embodiment provides a compound ofFormula (XVI), wherein R⁶ is an aryl.

Another embodiment provides a compound of Formula (XVI), wherein Y is abond. Another embodiment provides a compound of Formula (XVI), wherein Yis a —CH₂—. Another embodiment provides a compound of Formula (XVI),wherein Z is —SO₂R²¹. Another embodiment provides a compound of Formula(XVI), wherein Z is —N(R²²)SO₂R²¹. Another embodiment provides acompound of Formula (XVI), wherein Z is —SO₂N(R²²)₂. Another embodimentprovides a compound of Formula (XVI), wherein Z is —N(R²²)SO₂N(R²²)₂.Another embodiment provides a compound of Formula (XVI), wherein Z is—CON(R²²)₂. Another embodiment provides a compound of Formula (XVI),wherein Z is —N(R²²)CO₂R²¹. Another embodiment provides a compound ofFormula (XVI), wherein Z is —N(R²²)CON(R²²)₂. Another embodimentprovides a compound of Formula (XVI), wherein R²¹ is alkyl, cycloalkyl,or cycloalkylalkyl. Another embodiment provides a compound of Formula(XVI), wherein R²¹ is alkyl. Another embodiment provides a compound ofFormula (XVI), wherein R¹⁴ is hydrogen, halogen, or alkyl. Anotherembodiment provides a compound of Formula (XVI), wherein X4 is C—R¹⁵.Another embodiment provides a compound of Formula (XVI), wherein W is—O—. Another embodiment provides a compound of Formula (XVI), wherein Wis —NH—. Another embodiment provides a compound of Formula (XVI),wherein X is alkyl. Another embodiment provides a compound of Formula(XVI), wherein X is aryl. Another embodiment provides a compound ofFormula (XVI), wherein X is cycloalkylalkyl. Another embodiment providesa compound of Formula (XVI), wherein W is —O— and X is alkyl. Anotherembodiment provides a compound of Formula (XVI), wherein W is —O— and Xis aryl. Another embodiment provides a compound of Formula (XVI),wherein W is —O— and X is cycloalkylalkyl. Another embodiment provides acompound of Formula (XVI), wherein R⁵ and R⁸ are hydrogen. Anotherembodiment provides a compound of Formula (XVI), wherein R⁵ and R⁸ arehydrogen, and R⁶ is heteroaryl.

One embodiment provides a compound of Formula (XVII), or apharmaceutically acceptable salt thereof,

-   -   wherein,    -   R² is CH₃, CH₂CH₃, CH₂CF₃, CH₂F, CHF₂, CF₃, CH₂D, CHD₂, or CD₃;    -   X6 is C—H or N;    -   X5 is C—R⁵ or N; provided that if X6 is N, then X5 is C—R⁵, and        if X5 is N, then X6 is CH;    -   R⁵ is hydrogen, halogen, —OH, —CN, —OR⁶¹, —NHR⁶¹, —N(R⁶¹)₂,        alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,        heterocyclylalkyl, heteroaryl, or heteroarylalkyl, wherein each        R⁶¹ is independently selected from alkyl, cycloalkyl,        cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,        heteroaryl, or heteroarylalkyl;    -   R⁶ is hydrogen, halogen, —OH, —CN, alkyl, alkynyl, cycloalkyl,        cycloalkylalkyl, cycloalkylalkynyl, amino, alkylamino,        dialkylamino, heterocyclyl, cycloalkylalkylamino, alkoxy,        cycloalkyloxy, cycloalkylalkoxy, alkyl-S—, cycloalkyl-S—, and        cycloalkylalkyl-S—;    -   R^(A) is

-   -   X2 is N or C—R¹², wherein R¹² is hydrogen, halogen, alkyl, or        alkoxy;    -   R¹³ is —Y—Z;    -   Y is selected from a bond, —CH₂—, or —CH(C₁-C₄ alkyl)-;    -   Z is selected from —SO₂R²¹, —N(R²²)SO₂R²¹, —SO₂N(R²²)₂,        —N(R²²)SO₂N(R²²)₂, —CON(R²²)₂, —N(R²²)CO₂R²¹, —N(R²²)CON(R²²)₂,        —N(R²²)COR²¹, —OC(O)N(R²²)₂, —OSO₂N(R²²)₂, or —N(R²²)SO₃R²¹;    -   X3 is S;    -   X4 is N or C—R¹⁴, wherein R¹⁴ is hydrogen, halogen, alkyl, or        alkoxy;    -   R¹⁶ is hydrogen, halogen, or —W—X, wherein W is a bond, —O—,        —S—, or —NH—, and X is selected from alkyl, alkynyl, aryl,        aralkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkynyl,        heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;    -   each R²¹ is independently selected from alkyl, cycloalkyl,        cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,        heteroaryl, or heteroarylalkyl; and    -   each R²² is independently selected from hydrogen, alkyl,        cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,        heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

Another embodiment provides a compound of Formula (XVII), wherein RA is

Another embodiment provides a compound of Formula (XVII), wherein RA is

and X2 is N.

Another embodiment provides a compound of Formula (XVII), wherein RA is

and X2 is C—R¹².

Another embodiment provides a compound of Formula (XVII), wherein RA is

Another embodiment provides a compound of Formula (XVII), wherein RA is

and X4 is N.

Another embodiment provides a compound of Formula (XVII), wherein RA is

and X4 is C—R¹⁴.

Another embodiment provides a compound of Formula (XVII), wherein R² isCH₃. Another embodiment provides a compound of Formula (XVII), whereinX6 is C—H. Another embodiment provides a compound of Formula (XVII),wherein X6 is N. Another embodiment provides a compound of Formula(XVII), wherein X5 is C—R⁵. Another embodiment provides a compound ofFormula (XVII), wherein X5 is N. Another embodiment provides a compoundof Formula (XVII), wherein R⁵ is hydrogen, halogen, or alkyl. Anotherembodiment provides a compound of Formula (XVII), wherein R⁶ ishydrogen, halogen, or alkyl. Another embodiment provides a compound ofFormula (XVII), wherein R⁶ is heterocyclyl. Another embodiment providesa compound of Formula (XVII), wherein R⁶ is cycloalkylalkynyl. Anotherembodiment provides a compound of Formula (XVII), wherein R⁶ is alkoxy,cycloalkyloxy, or cycloalkylalkoxy.

Another embodiment provides a compound of Formula (XVII), wherein Y is abond. Another embodiment provides a compound of Formula (XVII), whereinY is a —CH₂—. Another embodiment provides a compound of Formula (XVII),wherein Z is —SO₂R²¹. Another embodiment provides a compound of Formula(XVII), wherein Z is —N(R²²)SO₂R²¹. Another embodiment provides acompound of Formula (XVII), wherein Z is —SO₂N(R²²)₂. Another embodimentprovides a compound of Formula (XVII), wherein Z is —N(R²²)SO₂N(R²²)₂.Another embodiment provides a compound of Formula (XVII), wherein Z is—CON(R²²)₂. Another embodiment provides a compound of Formula (XVII),wherein Z is —N(R²²)CO₂R²¹. Another embodiment provides a compound ofFormula (XVII), wherein Z is —N(R²²)CON(R²²)₂. Another embodimentprovides a compound of Formula (XVII), wherein R²¹ is alkyl, cycloalkyl,or cycloalkylalkyl. Another embodiment provides a compound of Formula(XVII), wherein R²¹ is alkyl. Another embodiment provides a compound ofFormula (XVII), wherein W is —O—. Another embodiment provides a compoundof Formula (XVII), wherein W is —NH—. Another embodiment provides acompound of Formula (XVII), wherein X is alkyl. Another embodimentprovides a compound of Formula (XVII), wherein X is alkynyl. Anotherembodiment provides a compound of Formula (XVII), wherein X is aryl.Another embodiment provides a compound of Formula (XVII), wherein X iscycloalkylalkyl. Another embodiment provides a compound of Formula(XVII), wherein X is cycloalkylalkynyl. Another embodiment provides acompound of Formula (XVII), wherein W is —O— and X is alkyl. Anotherembodiment provides a compound of Formula (XVII), wherein W is —O— and Xis alkynyl. Another embodiment provides a compound of Formula (XVII),wherein W is —O— and X is aryl. Another embodiment provides a compoundof Formula (XVII), wherein W is —O— and X is cycloalkylalkyl. Anotherembodiment provides a compound of Formula (XVII), wherein W is —O— and Xis cycloalkylalkynyl. Another embodiment provides a compound of Formula(XVII), wherein the R⁶ is CD₃.

One embodiment provides a compound of Formula (XVIII), or apharmaceutically acceptable salt thereof,

-   -   wherein,    -   R² is CH₃, CH₂CH₃, CH₂CF₃, CH₂F, CHF₂, CF₃, CH₂D, CHD₂, or CD₃;    -   X1 is C—H or N;    -   ring B is an optionally substituted 5- or 6-membered        heterocyclic ring containing at least one oxygen or nitrogen        atom;    -   R^(A) is

-   -   X2 is N or C—R¹², wherein R¹² is hydrogen, halogen, alkyl, or        alkoxy;    -   R¹³ is —Y—Z;    -   Y is selected from a bond, —CH₂—, or —CH(C₁-C₄ alkyl)-;    -   Z is selected from —SO₂R²¹, —N(R²²)SO₂R²¹, —SO₂N(R²²)₂,        —N(R²²)SO₂N(R²²)₂, —CON(R²²)₂, —N(R²²)CO₂R²¹, —N(R²²)CON(R²²)₂,        —N(R²²)COR²¹, —OC(O)N(R²²)₂, —OSO₂N(R²²)₂, or —N(R²²)SO₃R²¹;    -   X3 is S;    -   X4 is N or C—R¹⁴, wherein R¹⁴ is hydrogen, halogen, alkyl, or        alkoxy;    -   R¹⁶ is hydrogen, halogen, or —W—X, wherein W is a bond, —O—,        —S—, or —NH—, and X is selected from alkyl, alkynyl, aryl,        aralkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkynyl,        heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;    -   each R²¹ is independently selected from alkyl, cycloalkyl,        cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,        heteroaryl, or heteroarylalkyl; and    -   each R²² is independently selected from hydrogen, alkyl,        cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,        heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

One embodiment provides a compound of Formula (XIX), or apharmaceutically acceptable salt thereof,

-   -   wherein,    -   Q is N and T is C, or Q is C and T is N;    -   Ring B is an optionally substituted 5-membered aromatic        nitrogen-containing heteroaryl ring containing one or more        nitrogen atoms;    -   R² is selected from CH₃, CH₂CH₃, CH₂CF₃, CH₂F, CHF₂, CF₃, CH₂D,        CHD₂, or CD₃;    -   X1 is C—H or N;    -   R^(A) is

-   -   X2 is N or C—R¹², wherein R¹² is hydrogen, halogen, alkyl, or        alkoxy;    -   R¹³ is —Y—Z;    -   Y is selected from a bond, —CH₂—, or —CH(C₁-C₄ alkyl)-;    -   Z is selected from —SO₂R²¹, —N(R²²)SO₂R²¹, —SO₂N(R²²)₂,        —N(R²²)SO₂N(R²²)₂, —CON(R²²)₂, —N(R²²)CO₂R²¹, —N(R²²)CON(R²²)₂,        —N(R²²)COR²¹, —OC(O)N(R²²)₂, —OSO₂N(R²²)₂, or —N(R²²)SO₃R²¹;    -   X3 is S;    -   X4 is N or C—R¹⁴, wherein R¹⁴ is hydrogen, halogen, alkyl, or        alkoxy;    -   R¹⁶ is hydrogen, halogen, or —W—X, wherein W is a bond, —O—,        —S—, or —NH—, and X is selected from alkyl, alkynyl, aryl,        aralkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkynyl,        heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;    -   each R²¹ is independently selected from alkyl, cycloalkyl,        cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,        heteroaryl, or heteroarylalkyl; and    -   each R²² is independently selected from hydrogen, alkyl,        cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,        heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

Another embodiment provides a compound of Formula (XIX), wherein X2 isN. Another embodiment provides a compound of Formula (XIX), wherein X4is N. Another embodiment provides a compound of Formula (XIX), whereinX2 is C—R¹². Another embodiment provides a compound of Formula (XIX),wherein X4 is C—R¹⁴.

Another embodiment provides a compound of Formula (XIX), wherein thecompound of Formula (XIX) is selected from the group:

Another embodiment provides a compound of Formula (XIX), wherein Q is Nand T is C. Another embodiment provides a compound of Formula (XIX),wherein Q is C and T is N. Another embodiment provides a compound ofFormula (XIX), wherein R² is CH₃. Another embodiment provides a compoundof Formula (XIX), wherein X1 is C—H. Another embodiment provides acompound of Formula (XIX), wherein X1 is N.

Another embodiment provides a compound of Formula (XIX), wherein Y is abond. Another embodiment provides a compound of Formula (XIX), wherein Yis a —CH₂—. Another embodiment provides a compound of Formula (XIX),wherein Z is —SO₂R²¹. Another embodiment provides a compound of Formula(XIX), wherein Z is —N(R²²)SO₂R²¹. Another embodiment provides acompound of Formula (XIX), wherein Z is —SO₂N(R²²)₂. Another embodimentprovides a compound of Formula (XIX), wherein Z is —N(R²²)SO₂N(R²²)₂.Another embodiment provides a compound of Formula (XIX), wherein Z is—CON(R²²)₂. Another embodiment provides a compound of Formula (XIX),wherein Z is —N(R²²)CO₂R²¹. Another embodiment provides a compound ofFormula (XIX), wherein Z is —N(R²²)CON(R²²)₂. Another embodimentprovides a compound of Formula (XIX), wherein R²¹ is alkyl, cycloalkyl,or cycloalkylalkyl. Another embodiment provides a compound of Formula(XIX), wherein R²¹ is alkyl

Another embodiment provides a compound of Formula (XIX), wherein W is—O—. Another embodiment provides a compound of Formula (XIX), wherein Wis —NH—. Another embodiment provides a compound of Formula (XIX),wherein X is alkyl. Another embodiment provides a compound of Formula(XIX), wherein X is aryl. Another embodiment provides a compound ofFormula (XIX), wherein X is cycloalkylalkyl. Another embodiment providesa compound of Formula (XIX), wherein W is —O— and X is alkyl. Anotherembodiment provides a compound of Formula (XIX), wherein W is —O— and Xis aryl. Another embodiment provides a compound of Formula (XIX),wherein W is —O— and X is cycloalkylalkyl.

One embodiment provides a compound of Formula (XX), or apharmaceutically acceptable salt thereof,

-   -   wherein,    -   Ring B is an optionally substituted 5-membered heteroaryl ring        containing at least one oxygen or sulfur atom;    -   R² is selected from CH₃, CH₂CH₃, CH₂CF₃, CH₂F, CHF₂, CF₃, CH₂D,        CHD₂, or CD₃;    -   X1 is C—H or N;    -   R^(A) is

-   -   X2 is N or C—R¹², wherein R¹² is hydrogen, halogen, alkyl, or        alkoxy;    -   R¹³ is —Y—Z;    -   Y is selected from a bond, —CH₂—, or —CH(C₁-C₄ alkyl)-;    -   Z is selected from —SO₂R²¹, —N(R²²)SO₂R²¹, —SO₂N(R²²)₂,        —N(R²²)SO₂N(R²²)₂, —CON(R²²)₂, —N(R²²)CO₂R²¹, —N(R²²)CON(R²²)₂,        —N(R²²)COR²¹, —OC(O)N(R²²)₂, —OSO₂N(R²²)₂, or —N(R²²)SO₃R²¹;    -   X3 is S;    -   X4 is N or C—R¹⁴, wherein R¹⁴ is hydrogen, halogen, alkyl, or        alkoxy;    -   R¹⁶ is hydrogen, halogen, or —W—X, wherein W is a bond, —O—,        —S—, or —NH—, and X is selected from alkyl, alkynyl, aryl,        aralkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkynyl,        heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;    -   each R²¹ is independently selected from alkyl, cycloalkyl,        cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,        heteroaryl, or heteroarylalkyl; and    -   each R²² is independently selected from hydrogen, alkyl,        cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,        heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

Another embodiment provides a compound of Formula (XX), wherein X2 is N.Another embodiment provides a compound of Formula (XX), wherein X4 is N.Another embodiment provides a compound of Formula (XX), wherein X2 isC—R¹². Another embodiment provides a compound of Formula (XX), whereinX4 is C—R¹⁴.

Another embodiment provides a compound of Formula (XX), wherein thecompound of Formula (XX) has a formula selected from:

-   -   wherein each R³⁰ is independently selected from hydrogen,        halogen, —CN, C₁-C₄ alkyl, —OH, —OR³¹, —NHR³¹, —N(R³¹)₂,        —CONHR³¹, —CON(R³¹)₂; and R³¹ is C₁-C₄ alkyl.

Another embodiment provides a compound of Formula (XX), wherein thecompound of Formula (XX) has a formula selected from:

-   -   wherein each R³⁰ is independently selected from hydrogen,        halogen, —CN, C₁-C₄ alkyl, —OH, —OR³¹, —NHR³¹, —N(R³¹)₂,        —CONHR³¹, —CON(R³¹)₂; and R³¹ is C₁-C₄ alkyl.

Another embodiment provides a compound of Formula (XX), wherein thecompound of Formula (XX) has a formula selected from:

-   -   wherein each R³⁰ is independently selected from hydrogen,        halogen, —CN, C₁-C₄ alkyl, —OH, —OR³¹, —NHR³¹, —N(R³¹)₂,        —CONHR³¹, —CON(R³¹)₂; and R³¹ is C₁-C₄ alkyl.

Another embodiment provides a compound of Formula (XX), wherein R2 isCH3. Another embodiment provides a compound of Formula (XX), wherein X1is C—H. Another embodiment provides a compound of Formula (XX), whereinX1 is N.

Another embodiment provides a compound of Formula (XX), wherein Y is abond. Another embodiment provides a compound of Formula (XX), wherein Yis a —CH₂—. Another embodiment provides a compound of Formula (XX),wherein Z is —SO₂R²¹. Another embodiment provides a compound of Formula(XX), wherein Z is —N(R²²)SO₂R²¹. Another embodiment provides a compoundof Formula (XX), wherein Z is —SO₂N(R²²)₂. Another embodiment provides acompound of Formula (XX), wherein Z is —N(R²²)SO₂N(R²²)₂. Anotherembodiment provides a compound of Formula (XX), wherein Z is —CON(R²²)₂.Another embodiment provides a compound of Formula (XX), wherein Z is—N(R²²)CO₂R²¹. Another embodiment provides a compound of Formula (XX),wherein Z is —N(R²²)CON(R²²)₂. Another embodiment provides a compound ofFormula (XX), wherein R²¹ is alkyl, cycloalkyl, or cycloalkylalkyl.Another embodiment provides a compound of Formula (XV), wherein R²¹ isalkyl.

Another embodiment provides a compound of Formula (XX), wherein W is—O—. Another embodiment provides a compound of Formula (XX), wherein Wis —NH—. Another embodiment provides a compound of Formula (XX), whereinX is alkyl. Another embodiment provides a compound of Formula (XX),wherein X is alkynyl. Another embodiment provides a compound of Formula(XX), wherein X is aryl. Another embodiment provides a compound ofFormula (XX), wherein X is cycloalkylalkyl. Another embodiment providesa compound of Formula (XX), wherein X is cycloalkylalkynyl. Anotherembodiment provides a compound of Formula (XX), wherein W is —O— and Xis alkyl. Another embodiment provides a compound of Formula (XX),wherein W is —O— and X is aryl. Another embodiment provides a compoundof Formula (XX), wherein W is —O— and X is alkynyl. Another embodimentprovides a compound of Formula (XX), wherein W is —O— and X iscycloalkylalkyl. Another embodiment provides a compound of Formula (XX),wherein W is —O— and X is cycloalkylalkynyl.

One embodiment provides a compound of Formula (XXI), or apharmaceutically acceptable salt thereof,

-   -   wherein,    -   R² is CH₃, CH₂CH₃, CH₂CF₃, CH₂F, CHF₂, CF₃, CH₂D, CHD₂, or CD₃;    -   X1 is C—H or N;    -   ring B is an optionally substituted 5- or 6-membered        heterocyclic ring containing at least one oxygen or nitrogen        atom;    -   R^(A) is

-   -   R¹² is hydrogen or C₁-C₄ alkyl;    -   R¹³ is —Y—Z;    -   Y is selected from —CH₂—, or —CH(C₁-C₄ alkyl)-;    -   Z is selected from —SO₂R²¹, —SO₂N(R²²)₂, or —CON(R²²)₂;    -   R¹⁵ is hydrogen, halogen or C₁-C₄ alkyl;    -   R¹⁶ is hydrogen, halogen, or —W—X, wherein W is a bond, —O—,        —S—, or —NH—, and X is selected from alkyl, alkynyl, aryl,        aralkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkynyl,        heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;        or optionally, R¹⁶ and R¹⁵ connect to form a ring;    -   each R²¹ is independently selected from alkyl, cycloalkyl,        cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,        heteroaryl, or heteroarylalkyl; and    -   each R²² is independently selected from hydrogen, alkyl,        cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,        heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

One embodiment provides a compound of Formula (XXII), or apharmaceutically acceptable salt thereof,

-   -   wherein,    -   Q is N and T is C, or Q is C and T is N;    -   Ring B is an optionally substituted 5-membered aromatic        nitrogen-containing heteroaryl ring containing one or more        nitrogen atoms;    -   R² is selected from CH₃, CH₂CH₃, CH₂CF₃, CH₂F, CHF₂, CF₃, CH₂D,        CHD₂, or CD₃;    -   X1 is C—H or N;    -   R^(A) is

-   -   R¹² is hydrogen or C₁-C₄ alkyl;    -   R¹³ is —Y—Z;    -   Y is selected from —CH₂—, or —CH(C₁-C₄ alkyl)-;    -   Z is selected from —SO₂R²¹, —SO₂N(R²²)₂, or —CON(R²²)₂;    -   R¹⁵ is hydrogen, halogen or C₁-C₄ alkyl;    -   R¹⁶ is hydrogen, halogen, or —W—X, wherein W is a bond, —O—,        —S—, or —NH—, and X is selected from alkyl, alkynyl, aryl,        aralkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkynyl,        heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;        or optionally, R¹⁶ and R¹⁵ connect to form a ring;    -   each R²¹ is independently selected from alkyl, cycloalkyl,        cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,        heteroaryl, or heteroarylalkyl; and    -   each R²² is independently selected from hydrogen, alkyl,        cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,        heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

Another embodiment provides a compound of Formula (XXII), wherein thecompound of Formula (XXII) is selected from the group:

Another embodiment provides a compound of Formula (XXII), wherein Q is Nand T is C. Another embodiment provides a compound of Formula (XXII),wherein Q is C and T is N. Another embodiment provides a compound ofFormula (XXII), wherein R² is CH₃. Another embodiment provides acompound of Formula (XXII), wherein X1 is C—H. Another embodimentprovides a compound of Formula (XXII), wherein X1 is N.

Another embodiment provides a compound of Formula (XXII), wherein Y is a—CH₂—. Another embodiment provides a compound of Formula (XXII), whereinZ is —SO₂R²¹. Another embodiment provides a compound of Formula (XXII),wherein Z is —SO₂N(R²²)₂. Another embodiment provides a compound ofFormula (XXII), wherein Z is —CON(R²²)₂. Another embodiment provides acompound of Formula (XXII), wherein R²¹ is alkyl, cycloalkyl, orcycloalkylalkyl. Another embodiment provides a compound of Formula(XXII), wherein R²¹ is alkyl.

Another embodiment provides a compound of Formula (XXII), wherein W is—O—. Another embodiment provides a compound of Formula (XXII), wherein Wis —NH—. Another embodiment provides a compound of Formula (XXII),wherein X is alkyl. Another embodiment provides a compound of Formula(XXII), wherein X is aryl. Another embodiment provides a compound ofFormula (XXII), wherein X is cycloalkylalkyl. Another embodimentprovides a compound of Formula (XXII), wherein W is —O— and X is alkyl.Another embodiment provides a compound of Formula (XXII), wherein W is—O— and X is aryl. Another embodiment provides a compound of Formula(XXII), wherein W is —O— and X is cycloalkylalkyl.

One embodiment provides a compound of Formula (XXIII), or apharmaceutically acceptable salt thereof,

-   -   wherein,    -   Ring B is an optionally substituted 5-membered heteroaryl ring        containing at least one oxygen or sulfur atom;    -   R² is selected from CH₃, CH₂CH₃, CH₂CF₃, CH₂F, CHF₂, CF₃, CH₂D,        CHD₂, or CD₃;    -   X1 is C—H or N;    -   R^(A) is

-   -   R¹² is hydrogen or C₁-C₄ alkyl;    -   R¹³ is —Y—Z;    -   Y is selected from —CH₂—, or —CH(C₁-C₄ alkyl)-;    -   Z is selected from —SO₂R²¹, —SO₂N(R²²)₂, or —CON(R²²)₂;    -   R¹⁵ is hydrogen, halogen or C₁-C₄ alkyl;    -   R¹⁶ is hydrogen, halogen, or —W—X, wherein W is a bond, —O—,        —S—, or —NH—, and X is selected from alkyl, alkynyl, aryl,        aralkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkynyl,        heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;        or optionally, R¹⁶ and R¹⁵ connect to form a ring;    -   each R²¹ is independently selected from alkyl, cycloalkyl,        cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,        heteroaryl, or heteroarylalkyl; and    -   each R²² is independently selected from hydrogen, alkyl,        cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,        heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

Another embodiment provides a compound of Formula (XXIII), wherein thecompound of Formula (XXIII) has a formula selected from:

-   -   wherein each R³⁰ is independently selected from hydrogen,        halogen, —CN, C₁-C₄ alkyl, —OH, —OR³¹, —NHR³¹, —N(R³¹)₂,        —CONHR³¹, —CON(R³¹)₂; and R³¹ is C₁-C₄ alkyl.

Another embodiment provides a compound of Formula (XXIII), wherein thecompound of Formula (XXIII) has a formula selected from:

-   -   wherein each R³⁰ is independently selected from hydrogen,        halogen, —CN, C₁-C₄ alkyl, —OH, —OR³¹, —NHR³¹, —N(R³¹)₂,        —CONHR³¹, —CON(R³¹)₂; and R³¹ is C₁-C₄ alkyl.

Another embodiment provides a compound of Formula (XXIII), wherein thecompound of Formula (XXIII) has a formula selected from:

-   -   wherein each R³⁰ is independently selected from hydrogen,        halogen, —CN, C₁-C₄ alkyl, —OH, —OR³¹, —NHR³¹, —N(R³¹)₂,        —CONHR³¹, —CON(R³¹)₂; and R³¹ is C₁-C₄ alkyl.

Another embodiment provides a compound of Formula (XXIII), wherein R² isCH₃. Another embodiment provides a compound of Formula (XXIII), whereinX1 is C—H. Another embodiment provides a compound of Formula (XXIII),wherein X1 is N.

Another embodiment provides a compound of Formula (XXIII), wherein Y isa —CH₂—. Another embodiment provides a compound of Formula (XXIII),wherein Z is —SO₂R²¹. Another embodiment provides a compound of Formula(XXIII), wherein Z is —SO₂N(R²²)₂. Another embodiment provides acompound of Formula (XXIII), wherein Z is —CON(R²²)₂. Another embodimentprovides a compound of Formula (XXIII), wherein R²¹ is alkyl,cycloalkyl, or cycloalkylalkyl. Another embodiment provides a compoundof Formula (XXIII), wherein R²¹ is alkyl.

Another embodiment provides a compound of Formula (XXIII), wherein W is—O—. Another embodiment provides a compound of Formula (XXIII), whereinW is —NH—. Another embodiment provides a compound of Formula (XXIII),wherein X is alkyl. Another embodiment provides a compound of Formula(XXIII), wherein X is alkynyl. Another embodiment provides a compound ofFormula (XXIII), wherein X is aryl. Another embodiment provides acompound of Formula (XXIII), wherein X is cycloalkylalkyl. Anotherembodiment provides a compound of Formula (XXIII), wherein X iscycloalkylalkynyl. Another embodiment provides a compound of Formula(XXIII), wherein W is —O— and X is alkyl. Another embodiment provides acompound of Formula (XXIII), wherein W is —O— and X is aryl. Anotherembodiment provides a compound of Formula (XXIII), wherein W is —O— andX is alkynyl. Another embodiment provides a compound of Formula (XXIII),wherein W is —O— and X is cycloalkylalkyl. Another embodiment provides acompound of Formula (XXIII), wherein W is —O— and X iscycloalkylalkynyl.

One embodiment provides a compound of Formula (XXIV), or apharmaceutically acceptable salt thereof,

-   -   wherein,    -   R¹³ is —Y—Z;    -   Y is selected from a bond, or —CH₂—;    -   Z is selected from —SO₂R²¹, —N(R²²)SO₂R²¹, —SO₂N(R²²)₂,        —N(R²²)SO₂N(R²²)₂, —CON(R²²)₂, —N(R²²)CO₂R²¹, —N(R²²)CON(R²²)₂,        —N(R²²)COR²¹, —COR²¹, —OC(O)N(R²²)₂, —OSO₂N(R²²)₂,        —N(R²²)SO₃R²¹, or —N(R²²)₂;    -   R¹⁴ is hydrogen, halogen, C₁-C₃ alkyl, or C₁-C₃ alkoxy;    -   R¹⁵ is halogen or U—V, wherein U is a bond, —O—, or —CH₂—; and V        is —CN, alkyl, alkynyl, aryl, aralkyl, cycloalkyl,        cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or        heteroarylalkyl;    -   R¹⁶ is hydrogen;    -   each R²¹ is independently selected from alkyl, cycloalkyl,        cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,        heteroaryl, or heteroarylalkyl;    -   each R²² is independently selected from hydrogen, alkyl,        cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,        heterocyclylalkyl, heteroaryl, or heteroarylalkyl;    -   R^(B) is

-   -   -   wherein        -   R² is CH₃;        -   X5 is C—H;        -   X6 is C—R⁶;        -   X7 is C—R⁷;        -   X8 is C—H;        -   R⁶ is hydrogen, or halogen;        -   R⁷ is hydrogen, or halogen; or

    -   R^(B) is

-   -   -   wherein        -   R² is CH₃;        -   X6 is C—H;        -   X5 is C—R⁵;        -   R⁵ is hydrogen, or halogen;        -   R⁶ is hydrogen, alkyl, alkoxy, or halogen; or

    -   R^(B) is

-   -   -   wherein        -   Ring B is an optionally substituted 5-membered heteroaryl            ring containing at least one oxygen or sulfur atom;        -   R² is CH₃; and        -   X1 is C—H.

Another embodiment provides a compound of Formula (XXIV), or apharmaceutically acceptable salt thereof, wherein Y is —CH₂—. Anotherembodiment provides a compound of Formula (XXIV), or a pharmaceuticallyacceptable salt thereof, wherein Y is a bond.

Another embodiment provides a compound of Formula (XXIV), or apharmaceutically acceptable salt thereof, wherein Z is —SO₂R²¹,—N(R²²)SO₂R²¹, or —N(R²²)₂.

Another embodiment provides a compound of Formula (XXIV), or apharmaceutically acceptable salt thereof, wherein Z is —SO₂R²¹ or—N(R²²)SO₂R²¹. Another embodiment provides a compound of Formula (XXIV),or a pharmaceutically acceptable salt thereof, wherein Z is—N(R²²)SO₂R²¹. Another embodiment provides a compound of Formula (XXIV),or a pharmaceutically acceptable salt thereof, wherein Z is —SO₂R²¹.

Another embodiment provides a compound of Formula (XXIV), or apharmaceutically acceptable salt thereof, wherein R²¹ is heterocyclyl orheterocyclylalkyl. Another embodiment provides a compound of Formula(XXIV), or a pharmaceutically acceptable salt thereof, wherein R²¹ isalkyl, cycloalkyl, or cycloalkylalkyl. Another embodiment provides acompound of Formula (XXIV), or a pharmaceutically acceptable saltthereof, wherein R²¹ is alkyl, and the alkyl is a C₁-C₄ alkyl.

Another embodiment provides a compound of Formula (XXIV), or apharmaceutically acceptable salt thereof, wherein R²² is alkyl,cycloalkyl, or aralkyl. Another embodiment provides a compound ofFormula (XXIV), or a pharmaceutically acceptable salt thereof, whereinR²² is hydrogen or methyl.

Another embodiment provides a compound of Formula (XXIV), or apharmaceutically acceptable salt thereof, wherein R¹⁴ is hydrogen.

Another embodiment provides a compound of Formula (XXIV), or apharmaceutically acceptable salt thereof, wherein U is a bond. Anotherembodiment provides a compound of Formula (XXIV), or a pharmaceuticallyacceptable salt thereof, wherein U is —O—.

Another embodiment provides a compound of Formula (XXIV), or apharmaceutically acceptable salt thereof, wherein U is —CH₂—.

Another embodiment provides a compound of Formula (XXIV), or apharmaceutically acceptable salt thereof, wherein V is alkyl. Anotherembodiment provides a compound of Formula (XXIV), or a pharmaceuticallyacceptable salt thereof, wherein V is aryl. Another embodiment providesa compound of Formula (XXIV), or a pharmaceutically acceptable saltthereof, wherein V is aralkyl. Another embodiment provides a compound ofFormula (XXIV), or a pharmaceutically acceptable salt thereof, wherein Vis cycloalkylalkyl. Another embodiment provides a compound of Formula(XXIV), or a pharmaceutically acceptable salt thereof, wherein V isheterocyclylalkyl. Another embodiment provides a compound of Formula(XXIV), or a pharmaceutically acceptable salt thereof, wherein V isheteroaryl. Another embodiment provides a compound of Formula (XXIV), ora pharmaceutically acceptable salt thereof, wherein V isheteroarylalkyl. Another embodiment provides a compound of Formula(XXIV), or a pharmaceutically acceptable salt thereof, wherein V isalkynyl.

Another embodiment provides a compound of Formula (XXIV), or apharmaceutically acceptable salt thereof, wherein Y is a bond, Z is—N(R²²)SO₂R²¹, U is —O—, and V is aryl, aralkyl or cycloalkylalkyl.Another embodiment provides a compound of Formula (XXIV), or apharmaceutically acceptable salt thereof, wherein Y is a bond, Z is—SO₂R²¹, U is —O—, and V is aryl, aralkyl or cycloalkylalkyl.

Another embodiment provides a compound of Formula (XXIV), or apharmaceutically acceptable salt thereof, wherein RB is

Another embodiment provides a compound of Formula (XXIV), or apharmaceutically acceptable salt thereof, wherein R⁶ is halogen, and R⁷is hydrogen. Another embodiment provides a compound of Formula (XXIV),or a pharmaceutically acceptable salt thereof, wherein R⁶ is hydrogen,and R⁷ is halogen. Another embodiment provides a compound of Formula(XXIV), or a pharmaceutically acceptable salt thereof, wherein R⁶ ishydrogen, and R⁷ is hydrogen.

Another embodiment provides a compound of Formula (XXIV), or apharmaceutically acceptable salt thereof, wherein RB is

Another embodiment provides a compound of Formula (XXIV), or apharmaceutically acceptable salt thereof, wherein R⁵ is hydrogen, and R⁶is alkyl. Another embodiment provides a compound of Formula (XXIV), or apharmaceutically acceptable salt thereof, wherein R⁶ is methyl.

Another embodiment provides a compound of Formula (XXIV), or apharmaceutically acceptable salt thereof, wherein RB is

Another embodiment provides a compound of Formula (XXIV), or apharmaceutically acceptable salt thereof, wherein Ring B is anoptionally substituted 5-membered heteroaryl ring containing one oxygen.

One embodiment provides a compound of Formula (XXV), or apharmaceutically acceptable salt thereof,

-   -   wherein,    -   Ring B is an optionally substituted 5-, 6-, or 7-membered,        non-aromatic carbocyclyl ring;    -   R² is selected from CH₃, CH₂CH₃, CH₂CF₃, CH₂F, CHF₂, CF₃, CH₂D,        CHD₂, or CD₃;    -   X3 is C—H or N;    -   R^(A) is

-   -   X2 is N or C—R¹², wherein R¹² is hydrogen, halogen, alkyl, or        alkoxy;    -   R¹³ is —Y—Z;    -   Y is selected from a bond, or —CH₂—;    -   Z is selected from —SO₂R²¹, —N(R²²)SO₂R²¹, —SO₂N(R²²)₂,        —N(R²²)SO₂N(R²²)₂, —CON(R²²)₂, —N(R²²)CO₂R²¹, —N(R²²)CON(R²²)₂,        —N(R²²)COR²¹, —OC(O)N(R²²)₂, —OSO₂N(R²²)₂, or —N(R²²)SO₃R²¹;    -   X3 is N or C—R¹⁴, wherein R¹⁴ is hydrogen, halogen, —CN, alkyl,        cycloalkyl, or alkoxy;    -   X4 is N or C—R¹⁵, wherein R¹⁵ is hydrogen, halogen, —CN, alkyl,        or alkoxy;    -   R¹⁶ is hydrogen, halogen, or —W—X, wherein W is a bond, —O—,        —S—, or —NH—, and X is selected from alkyl, aryl, aralkyl,        cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl,        heteroaryl, or heteroarylalkyl;    -   each R²¹ is independently selected from alkyl, cycloalkyl,        cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,        heteroaryl, or heteroarylalkyl; and    -   each R²² is independently selected from hydrogen, alkyl,        cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,        heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

Another embodiment provides a compound of Formula (XXV), or apharmaceutically acceptable salt thereof, wherein Ring B is anoptionally substituted 5-membered, non-aromatic carbocyclyl ring.Another embodiment provides a compound of Formula (XXV), or apharmaceutically acceptable salt thereof, wherein Ring B is anoptionally substituted 6-membered, non-aromatic carbocyclyl ring.Another embodiment provides a compound of Formula (XXV), or apharmaceutically acceptable salt thereof, wherein Ring B is anoptionally substituted 7-membered, non-aromatic carbocyclyl ring.

Another embodiment provides a compound of Formula (XXV), or apharmaceutically acceptable salt thereof, wherein R² is CH₃.

Another embodiment provides a compound of Formula (XXV), or apharmaceutically acceptable salt thereof, wherein X3 is C—H. Anotherembodiment provides a compound of Formula (XXV), or a pharmaceuticallyacceptable salt thereof, wherein X3 is N.

Another embodiment provides a compound of Formula (XXV), or apharmaceutically acceptable salt thereof, wherein Y is a bond. Anotherembodiment provides a compound of Formula (XXV), or a pharmaceuticallyacceptable salt thereof, wherein Y is a —CH₂—.

Another embodiment provides a compound of Formula (XXV), or apharmaceutically acceptable salt thereof, wherein Z is —SO₂R²¹. Anotherembodiment provides a compound of Formula (XXV), or a pharmaceuticallyacceptable salt thereof, wherein Z is —N(R²²)SO₂R²¹.

Another embodiment provides a compound of Formula (XXV), or apharmaceutically acceptable salt thereof, wherein Z is —SO₂N(R²²)₂.Another embodiment provides a compound of Formula (XXV), or apharmaceutically acceptable salt thereof, wherein Z is—N(R²²)SO₂N(R²²)₂. Another embodiment provides a compound of Formula(XXV), or a pharmaceutically acceptable salt thereof, wherein Z is—CON(R²²)₂. Another embodiment provides a compound of Formula (XXV), ora pharmaceutically acceptable salt thereof, wherein Z is —N(R²²)CO₂R²¹.Another embodiment provides a compound of Formula (XXV), or apharmaceutically acceptable salt thereof, wherein Z is —N(R²²)CON(R²²)₂.

Another embodiment provides a compound of Formula (XXV), or apharmaceutically acceptable salt thereof, wherein R²¹ is alkyl,cycloalkyl, or cycloalkylalkyl. Another embodiment provides a compoundof Formula (XXV), or a pharmaceutically acceptable salt thereof, whereinR²¹ is alkyl.

Another embodiment provides a compound of Formula (XXV), or apharmaceutically acceptable salt thereof, wherein R¹⁴ is hydrogen,halogen, or alkyl. Another embodiment provides a compound of Formula(XXV), or a pharmaceutically acceptable salt thereof, wherein X4 isC—R¹⁵. Another embodiment provides a compound of Formula (XXV), or apharmaceutically acceptable salt thereof, wherein W is —O—. Anotherembodiment provides a compound of Formula (XXV), or a pharmaceuticallyacceptable salt thereof, wherein W is —NH—.

Another embodiment provides a compound of Formula (XXV), or apharmaceutically acceptable salt thereof, wherein X is alkyl. Anotherembodiment provides a compound of Formula (XXV), or a pharmaceuticallyacceptable salt thereof, wherein X is aryl. Another embodiment providesa compound of Formula (XXV), or a pharmaceutically acceptable saltthereof, wherein X is cycloalkylalkyl.

Another embodiment provides a compound of Formula (XXV), or apharmaceutically acceptable salt thereof, wherein W is —O— and X isalkyl. Another embodiment provides a compound of Formula (XXV), or apharmaceutically acceptable salt thereof, wherein W is —O— and X isaryl. Another embodiment provides a compound of Formula (XXV), or apharmaceutically acceptable salt thereof, wherein W is —O— and X iscycloalkylalkyl.

In some embodiments, the substituted heterocyclic derivative compounddisclosed herein has the structure provided in Table 1.

TABLE 1 Chemical Synthesis Example Structure Name  2

4-(3-methoxyphenyl)-2- methylisoquinolin-1-one  3

4-(2-fluorophenyl)-2- methylisoquinolin-1-one  4

4-(2-methoxyphenyl)-2- methylisoquinolin-1-one  5

4-(3-aminophenyl)-2- methylisoquinolin-1-one  6

N-cyclopropyl-3-(2-methyl-1-oxoiso- quinolin-4-yl)benzenesulfonamide  7

2-methyl-4-(3-pyrrolidin-1-ylsulfonylphenyl) isoquinolin-1-one  8

N-[[3-(2-methyl-1-oxoisoquinolin-4-yl) phenyl]methyl]methanesulfonamide 9

N-[3-(2-methyl-1-oxoisoquinolin-4-yl) phenyl]methanesulfonamide  10

N-ethyl-3-(2-methyl-1-oxo-isoquinolin-4-yl) benzenesulfonamide  11

4-(3-ethylsulfonylphenyl)-2- methylisoquinolin-1-one  12

4-[3-(dimethylsulfamoylamino)phenyl]- 2-methyl-1-oxoisoquinoline  13

N-[3-(2-methyl-1-oxoisoquinolin-4-yl) phenyl]ethanesulfonamide  14

2-methyl-4-(3-morpholin-4-yl- sulfonylphenyl)isoquinolin-1-one  15

N-benzyl-2-methoxy-5-(2-methyl-1- oxoisoquinolin-4-yl)benzenesulfonamide 16

2-methoxy-5-(2-methyl-1-oxoisoquinolin-4-yl) benzenesulfonamide  17

N-[2-methyl-5-(2-methyl-1-oxoiso-quinolin-4-yl)phenyl]methanesulfonamide  18

N-benzyl-2-methoxy-5-(2-methyl-1- oxoisoquinolin-4-yl)benzamide  19

4-(3,4-dihydro-2H-1,4-benzoxazin-6-yl)-2- methylisoquinolin-1-one  20

2-methyl-4-(2-oxo-1,3-dihydroindo1-6- yl)isoquinolin-1-one  21

3-(2-methyl-1-oxoisoquinolin-4- yl)benzenesulfonamide  22

N-(2-hydroxyethyl)-3-(2-methyl-1- oxoisoquinolin-4-yl)benzenesulfonamide 23

4-(5-amino-2-fluorophenyl)-2- methylisoquinolin-1-one  24

4-(5-amino-2,4-difluorophenyl)-2- methylisoquinolin-1-one  25

4-(3-amino-5-fluorophenyl)-2- methylisoquinolin-1-one  26

4-(3-amino-4-fluorophenyl)-2- methylisoquinolin-1-one  27

N-benzyl-3-(2-methyl-1-oxoisoquinolin-4-yl) benzenesulfonamide  28

N-[3-(2-methyl-1-oxoisoquinolin-4-yl) phenyl]propane-1-sulfonamide  29

N-[3-(2-methyl-1-oxoisoquinolin-4-yl) phenyl]butane-1-sulfonamide  30

N-[2-methoxy-5-(2-methyl-1-oxoiso-quinolin-4-yl)phenyl]methanesulfonamide  31

tert-butyl N-methyl-N-[3-(2-methyl-1-oxoisoquinolin-4-yl)phenyl]carbamate  32

2-methyl-4-[3-(methylamino)phenyl] isoquinolin-1-one  33

N-methyl-N-[3-(2-methyl-1-oxoiso-quinolin-4-yl)phenyl]methanesulfonamide  34

N-[4-fluoro-3-(2-methyl-1-oxoisoquinolin-4-yl) phenyl]methanesulfonamide 35

N-[2,4-difluoro-5-(2-methyl-1-oxoisoquinolin-4-yl)phenyl]methanesulfonamide  36

N-[3-fluoro-5-(2-methyl-1-oxoisoquinolin-4-yl) phenyl]methanesulfonamide 37

N-[2-fluoro-5-(2-methyl-1-oxoisoquinolin-4-yl) phenyl]methanesulfonamide 38

N-[4-chloro-3-(2-methyl-1-oxoisoquinolin- 4-yl)phenyl]methanesulfonamide 39

N-[4-methyl-3-(2-methyl-1-oxoisoquinolin- 4-yl)phenyl]methanesulfonamide 40

N-[3-(2-methyl-1-oxoisoquinolin-4-yl)-5-(trifluoromethyl)phenyl]methanesulfonamide  41

N-[4-fluoro-3-[2-methyl-6-(1-methylpyrazol-4- yl)-1-oxoisoquinolin-4-yl]phenyl]methanesulfonamide  42

N-[3-[2-methyl-6-(1-methylpyrazol-4-yl)-1- oxoisoquinolin-4-yl]phenyl]methanesulfonamide  43

N-[2,4-difluoro-5-[2-methyl-6-(1-methylpyrazol-4-yl)-1-oxoisoquinolin-4-yl] phenyl]methanesulfonamide  44

4-(3-ethylsulfonylphenyl)-2-methyl-6-(1-methylpyrazol-4-yl)isoquinolin-1-one  45

N-[4-chloro-3-[2-methyl-6-(1-methylpyrazol- 4-yl)-1-oxoisoquinolin-4-yl]phenyl]ethanesulfonamide  46

4-[2-(cyclopropylmethoxy)-5- methylsulfonylphenyl]-2-methyl-6-(1-methylpyrazol-4-yl)isoquinolin-1-one  47

N-[3-(6-fluoro-2-methyl-1-oxoisoquinolin-4-yl) phenyl]methanesulfonamide 48

3-(6-fluoro-2-methyl-1-oxoisoquinolin-4-yl) benzenesulfonamide  49

N-ethyl-3-(6-fluoro-2-methyl-1- oxoisoquinolin-4-yl)benzenesulfonamide 50

N-[4-chloro-3-(6-fluoro-2-methyl-1-oxoisoquinolin-4-yl)phenyl]ethanesulfonamide  51

N-[3-(2-methyl-1-oxo-2,7-naphthyridin-4-yl) phenyl]methanesulfonamide 52

N-[3-(2-methyl-1-oxo-2,7-naphthyridin-4-yl) phenyl]ethanesulfonamide  53

N-ethyl-3-(2-methyl-1-oxo-2,7-naphthyridin- 4-yl)benzenesulfonamide  54

N-benzyl-2-methoxy-5-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)benzenesulfonamide  55

3-(2-methyl-1-oxo-2,7-naphthyridin-4-yl) benzenesulfonamide  56

2-methoxy-5-(2-methyl-1-oxo-2,7- naphthyridin-4-yl)benzenesulfonamide 57

N-[4-(2,4-difluorophenoxy)-3-(2-methyl-1- oxo-2,7-naphthyridin-4-yl)phenyl]ethanesulfonamide  58

N-[3-(7-fluoro-2-methyl-1-oxoisoquinolin-4-yl) phenyl]methanesulfonamide 59

N-ethyl-3-(7-fluoro-2-methyl-1- oxoisoquinolin-4-yl)benzenesulfonamide 60

N-benzyl-5-(7-fluoro-2-methyl-1- oxoisoquinolin-4-yl)-2-methoxybenzenesulfonamide  61

3-(7-fluoro-2-methyl-1-oxoisoquinolin-4- yl)benzenesulfonamide  62

N-[3-(7-fluoro-2-methyl-1-oxoisoquinolin-4- yl)phenyl]ethanesulfonamide 63

4-(3-ethylsulfonylphenyl)-7-fluoro-2- methylisoquinolin-1-one  64

5-(7-fluoro-2-methyl-1-oxoisoquinolin-4-yl)-2- methoxybenzenesulfonamide 65

2-methyl-4-(1-methylpyrazol-4-yl)isoquinolin- 1-one  66

4-(furan-2-yl)-2-methylisoquinolin-1-one  67

2-methyl-4-(1,3-oxazol-2-yl)isoquinolin- 1-one  68

2-methyl-4-(1H-pyrazol-5-yl)isoquinolin- 1-one  69

2-methyl-4-(1-methylimidazol-2- yl)isoquinolin-1-one  70

2-methyl-4-pyridin-2-ylisoquinolin-1-one  71

2-methyl-4-pyrimidin-2-ylisoquinolin- 1-one  72

N-[3-[2-methyl-6-(6-methylpyridin-3-yl)-1-oxoisoquinolin-4-yl]phenyl]ethanesulfonamide  73

N-[3-(2-methyl-1-oxo-6-phenylisoquinolin- 4-yl)phenyl]ethanesulfonamide 74

N-[3-(2-methyl-1-oxo-6-phenylisoquinolin- 4-yl)phenyl]methanesulfonamide 75

N-[3-(2,6-dimethyl-1-oxoisoquinolin-4-yl) phenyl]ethanesulfonamide  76

N-[3-(6-ethyl-2-methyl-1-oxoisoquinolin-4-yl) phenyl]ethanesulfonamide 77

N-[3-(6-ethyl-2-methyl-1-oxoisoquinolin-4-yl) phenyl]methanesulfonamide 78

N-[3-(2,6-dimethyl-1-oxoisoquinolin-4-yl) phenyl]methanesulfonamide  79

4-(5-ethylsulfonyl-2-methoxyphenyl)-2-methyl-6-(1-methylpyrazol-4-yl)isoquinolin- 1-one  80

4-(5-ethylsulfonyl-2-hydroxyphenyl)-2-methyl-6-(1-methylpyrazol-4-yl)isoquinolin-1-one  81

4-(2-ethoxy-5-ethylsulfonylphenyl)-2-methyl-6-(1-methylpyrazol-4-yl)isoquinolin-1-one  82

4-[2-(cyclopropylmethoxy)-5- ethylsulfonylphenyl]-2-methyl-6-(1-methylpyrazol-4-yl)isoquinolin-1-one  83

4-(5-ethylsulfonyl-2-propoxyphenyl)-2-methyl-6-(1-methylpyrazol-4-yl)isoquinolin-1-one  84

4-[5-ethylsulfonyl-2-(2- hydroxyethoxy)phenyl]-2-methyl-6-(1-methylpyrazol-4-yl)isoquinolin-1-one  85

4-[2-(2-aminoethoxy)-5-ethylsulfonylphenyl]-2-methyl-6-(1-methylpyrazol-4-yl) isoquinolin-1-one  86

N-[2-fluoro-4-methoxy-5-[2-methyl-6-(1-methylpyrazol-4-yl)-1-oxoisoquinolin-4- yl]phenyl]ethanesulfonamide  87

N-[3-(2-methyl-1-oxo-6-pyridin-2-ylisoquinolin-4-yl)phenyl]ethanesulfonamide  88

4-[4-fluoro-2-methoxy-5- (methylsulfonylmethyl)phenyl]-2-methyl-6-(1-methylpyrazol-4-yl)isoquinolin-1-one  89

4-[2-(cyclopropylmethoxy)- 5-methylsulfonylphenyl]-2-methylisoquinolin-1-one  90

4-[2-(cyclopropylmethoxy)-5- methylsulfonylphenyl]-6-fluoro-2-methylisoquinolin-1-one  91

4-[2-(cyclopropylmethoxy)-5- methylsulfonylphenyl]-7-fluoro-2-methylisoquinolin-1-one  92

4-[2-(2,4-difluorophenoxy)-5- methylsulfonylphenyl]-2-methylisoquinolin-1-one  93

N-[4-(2,4-difluorophenoxy)-3-(2-methyl-1- oxoisoquinolin-4-yl)phenyl]ethanesulfonamide  94

N-[3-(1-methyl-6-oxopyridin-3-yl) phenyl]methanesulfonamide  95

N-[3-(1,4-dimethyl-6-oxopyridin-3-yl) phenyl]methanesulfonamide  96

N-[3-(1,5-dimethyl-6-oxopyridin-3-yl) phenyl]methanesulfonamide  97

N-[3-(1,4,5-trimethyl-6-oxopyridin-3-yl) phenyl]methanesulfonamide  98

5-[2-(cyclopropylmethoxy)-5- methylsulfonylphenyl]-1-methylpyridin-2-one  99

N-[4-(2,4-difluorophenoxy)-3-(1-methyl-6-oxopyridin-3-yl)phenyl]ethanesulfonamide 100

N-[4-(2,4-difluorophenoxy)-3-(1-methyl-6-oxopyridin-3-yl)phenyl]methanesulfonamide 101

N-[4-(2,4-difluorophenoxy)-3-(1,4-dimethyl-6-oxopyridin-3-yl)phenyl]methanesulfonamide 102

N-[4-(2,4-difluorophenoxy)-3-(1,5-dimethyl-6-oxopyridin-3-yl)phenyl]methanesulfonamide 103

N-[4-(2,4-difluorophenoxy)-3-(1,4,5-trimethyl-6-oxopyridin-3-yl)phenyl]methanesulfonamide 104

3-amino-1-methyl-5-(3- methylsulfonylphenyl)pyrazin-2-one 105

3-amino-5-(3-ethylsulfonylphenyl)-1- methylpyrazin-2-one 106

N-[5-(6-amino-4-methyl-5-oxopyrazin-2-yl)-2-methoxyphenyl]methanesulfonamide 107

3-amino-1-methyl-5-(3- methylsulfonylphenyl)pyridin-2-one 108

3-amino-5-(3-ethylsulfonylphenyl)-1- methylpyridin-2-one 109

N-[5-(5-amino-1-methyl-6-oxopyridin-3-yl)-2-methoxyphenyl]methanesulfonamide 110

N-[2-methoxy-5-[1-methyl-5-(methylamino)-6-oxopyridin-3-yl]phenyl]methanesulfonamide 111

N-[5-[5-(ethylamino)-1-methyl-6-oxopyridin-3-yl]-2-methoxyphenyl]methanesulfonamide 112

N-[5-[5-(cyclopropylmethylamino)-1-methyl-6- oxopyridin-3-yl]-2-methoxyphenyl]methanesulfonamide 113

N-[5-[5-(dimethylamino)-1-methyl-6- oxopyridin-3-yl]-2-methoxyphenyl]methanesulfonamide 114

N-[5-[5-(diethylamino)-1-methyl-6-oxopyridin-3-yl]-2-methoxyphenyl]methanesulfonamide 115

N-[3-(5-amino-1-methyl-6-oxopyridin-3-yl)-4-(2,4-difluorophenoxy)phenyl] ethanesulfonamide 116

3-amino-5-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-1-methylpyridin-2-one 117

4-ethoxy-3-(1-methyl-6-oxopyridin-3-yl) benzenesulfonamide 118

4-(2,4-difluorophenoxy)-3-(1-methyl-6-oxopyridin-3-yl)benzenesulfonamide 119

5-[2-(cyclopropylmethoxy)-5- methylsulfonylphenyl]-3-fluoro-1-methylpyridin-2-one 120

5-[2-(2,4-difluorophenoxy)-5- methylsulfonylphenyl]-3-fluoro-1-methylpyridin-2-one 121

5-[2-(2,4-difluorophenoxy)-5- ethylsulfonylphenyl]-3-fluoro-1-methylpyridin-2-one 122

N-[4-(2,4-difluorophenoxy)-3-(5-fluoro-1- methyl-6-oxopyridin-3-yl)phenyl]ethanesulfonamide 123

N-[3-(2-methyl-1-oxo-2,6-naphthyridin-4-yl) phenyl]ethanesulfonamide 124

N-ethyl-3-(2-methyl-1-oxo-2,6-naphthyridin- 4-yl)benzenesulfonamide 125

N-[3-(2-methyl-1-oxo-2,6-naphthyridin-4-yl) phenyl]methanesulfonamide126

4-(3-ethylsulfonylphenyl)-2-methyl-2,6- naphthyridin-1-one 127

N-[4-(2,4-difluorophenoxy)-3-(2-methyl-1- oxo-2,6-naphthyridin-4-yl)phenyl]ethanesulfonamide 128

4-[2-(cyclopropylmethoxy)-5- methylsulfonylphenyl]-2-methyl-6-(4-methylpyrazol-1-yl)isoquinolin-1-one 129

N-[4-(2,4-difluorophenoxy)-3-(7-methyl-8- oxoimidazo[1,5-a]pyrazin-5-yl)phenyl]ethanesulfonamide 130

5-[2-(cyclopropylmethoxy)-5-methyl- sulfonylphenyl]-7-methylimidazo[1,5-a]pyrazin-8-one 131

7-methyl-5-(3-methylsulfonylphenyl) imidazo[1,5-a]pyrazin-8-one 132

N-[2-methoxy-5-(7-methyl-8- oxoimidazo[1,5-a]pyrazin-5-yl)phenyl]methanesulfonamide 133

5-(3-ethylsulfonylphenyl)-7- methylimidazo[1,5-a]pyrazin-8-one 134

N-[3-(5-chloro-1-methyl-6-oxopyridin-3-yl)-4- (2,4-difluorophenoxy)phenyl]ethanesulfonamide 135

4-[2-(cyclopropylmethoxy)-5- ethylsulfonylphenyl]-2-methylisoquinolin-1-one 136

6-[2-(cyclopropylmethoxy)-5- methylsulfonylphenyl]-2,4-dimethylpyridazin-3-one 137

6-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2,5-dimethylpyridazin- 3-one 138

N-[4-(2,4-difluorophenoxy)-3-[1-methyl-6-oxo-5-(trifluoromethyl)pyridin-3- yl]phenyl]ethanesulfonamide 139

N-[4-(2,4-difluorophenoxy)-3-(4-fluoro-1- methyl-6-oxopyridin-3-yl)phenyl]ethanesulfonamide 140

N-[3-(5-cyclopropyl-1-methyl-6-oxopyridin-3- yl)-4-(2,4-difluorophenoxy)phenyl]ethanesulfonamide 141

N-{4-(2,4-difluorophenoxy)-3-[1-(²H₃)methyl-6-oxopyridin-3-yl]phenyl}ethanesulfonamide 142

N-[4-(2,4-difluorophenoxy)-3-(2-methyl-1-oxo-5,6,7,8-tetrahydro-2,6-naphthyridin-4-yl) phenyl]ethanesulfonamide143

4-[5-(cyclopropylmethoxy)-2- (methylsulfonylmethyl)pyrimidin-4-yl]-2-methylisoquinolin-1-one 144

5-[5-(cyclopropylmethoxy)-2- (methylsulfonylmethyl)pyrimidin-4-yl]-1,3-dimethylpyridin-2-one 145

4-[5-(cyclopropylmethoxy)-2- (methylsulfonylmethyl)pyrimidin-4-yl]-2-methyl-6-(1-methylpyrazol-4-yl) isoquinolin-1-one 146

5-[5-(2,4-difluorophenoxy)-2- (methylsulfonylmethyl)pyrimidin-4-yl]-3-methoxy-1-methylpyridin-2-one 147

5-[5-(2,4-difluorophenoxy)-2- (methylsulfonylmethyl)pyrimidin-4-yl]-1,3-dimethylpyridin-2-one 148

4-[5-(2,4-difluorophenoxy)-2- (methylsulfonylmethyl)pyrimidin-4-yl]-2-methylisoquinolin-1-one 149

5-[5-(2,4-difluorophenoxy)-2- methylsulfonylpyrimidin-4-yl]-1,3-dimethylpyridin-2-one 150

5-[5-(2,4-difluorophenoxy)-2- methylsulfonylpyrimidin-4-yl]-3-methoxy-1-methylpyridin-2-one 151

4-[5-(2,4-difluorophenoxy)-2- methylsulfonylpyrimidin-4-yl]-2-methylisoquinolin-1-one 152

N-[5-(cyclopropylmethoxy)-4-(2-methyl-1-oxoisoquinolin-4-yl)pyrimidin-2-yl] methanesulfonamide 153

N-[5-(cyclopropylmethoxy)-4-(1,5-dimethyl-6-oxopyridin-3-yl)pyrimidin-2-yl] methanesulfonamide 154

N-[5-(cyclopropylmethoxy)-4-[2-methyl-6-(1-methylpyrazol-4-yl)-1-oxoisoquinolin-4-yl]pyrimidin-2-yl]methanesulfonamide 155

N-[5-(cyclopropylmethoxy)-4-(2-methyl-1-oxoisoquinolin-4-yl)pyrimidin-2-yl] ethanesulfonamide 156

4-[5-(cyclopropylmethoxy)-2-(1,1-dioxo-1,2-thiazolidin-2-yl)pyrimidin-4-yl]-2- methylisoquinolin-1-one 157

N-[5-(cyclopropylmethoxy)-4-(6-fluoro-2-methyl-1-oxoisoquinolin-4-yl)pyrimidin-2-yl] ethanesulfonamide 158

N-[5-(cyclopropylmethoxy)-4-(7-fluoro-2-methyl-1-oxoisoquinolin-4-yl)pyrimidin-2-yl] methanesulfonamide 159

N-[5-(cyclopropylmethoxy)-4-(6-fluoro-2-methyl-1-oxoisoquinolin-4-yl)pyrimidin-2-yl] methanesulfonamide 160

N-[5-(cyclopropylmethoxy)-4-(7-fluoro-2-methyl-1-oxoisoquinolin-4-yl)pyrimidin-2-yl] ethanesulfonamide 161

N-[5-(cyclopropylmethoxy)-4-(2-methyl-1-oxoisoquinolin-4-yl)pyrimidin-2-yl]-N- ethylmethanesulfonamide 162

N-[5-(cyclopropylmethoxy)-4-(1,5-dimethyl-6-oxopyridin-3-yl)pyrimidin-2-yl]-N- ethylmethanesulfonamide 163

N-[5-(cyclopropylmethoxy)-4-(2-methyl-1-oxo-5,6,7,8-tetrahydroisoquinolin-4-yl)pyrimidin-2-yl]methanesulfonamide 164

N-[5-(cyclopropylmethoxy)-4-(2-methyl-1-oxo-5,6,7,8-tetrahydroisoquinolin-4-yl) pyrimidin-2-yl]ethanesulfonamide165

N-[5-(2,4-difluorophenoxy)-4-(2-methyl-1-oxoisoquinolin-4-yl)pyrimidin-2-yl] methanesulfonamide 166

N-[5-(2,4-difluorophenoxy)-4-(1,5-dimethyl-6-oxopyridin-3-yl)pyrimidin-2-yl] methanesulfonamide 167

N-[5-(2,4-difluorophenoxy)-4-(5-methoxy-1-methyl-6-oxopyridin-3-yl)pyrimidin-2-yl] methanesulfonamide 168

N-[5-(2,4-difluorophenoxy)-4-(5-methoxy-1-methyl-6-oxopyridin-3-yl)pyrimidin-2-yl] ethanesulfonamide 169

N-[5-(2,4-difluorophenoxy)-4-(1,5-dimethyl-6-oxopyridin-3-yl)pyrimidin-2-yl] ethanesulfonamide 170

N-[5-(2,4-difluorophenoxy)-4-(2-methyl-1-oxoisoquinolin-4-yl)pyrimidin-2-yl] ethanesulfonamide 171

4-[5-(2,4-difluorophenoxy)-2-(1,1-dioxo-1,2-thiazolidin-2-yl)pyrimidin-4-yl]-2- methylisoquinolin-1-one 172

N-[5-(2,4-difluorophenoxy)-4-(2-methyl-1-oxo-5,6,7,8-tetrahydroisoquinolin-4-yl)pyrimidin-2-yl]methanesulfonamide 173

N-[5-(2,4-difluorophenoxy)-4-(2-methyl-1-oxo-5,6,7,8-tetrahydroisoquinolin-4-yl) pyrimidin-2-yl]ethanesulfonamide174

4-[2-(cyclopropylmethoxy)-5- ethylsulfonylphenyl]-6-fluoro-2-methylisoquinolin-1-one 175

2-methyl-4-[5-methylsulfonyl-2-(oxolan-3- yloxy)phenyl]isoquinolin-1-one176

2-methyl-4-[5-methylsulfonyl-2-(oxan-4- yloxy)phenyl]isoquinolin-1-one177

4-(2-ethoxy-5-methylsulfonylphenyl)-2- methylisoquinolin-1-one 178

2-methyl-4-(5-methylsulfonyl-2- propoxyphenyl)isoquinolin-1-one 179

2-methyl-4-[5-methylsulfonyl-2-(oxan-3- yloxy)phenyl]isoquinolin-1-one180

4-[2-(trans-4-hydroxycyclohexyl)oxy-5- methylsulfonylphenyl]-2-methylisoquinolin-1-one 181

4-[5-ethylsulfonyl-2-(trans-4- hydroxycyclohexyl)oxyphenyl]-2-methylisoquinolin-1-one 182

4-[2-(trans-4-aminocyclohexyl)oxy-5- methylsulfonylphenyl]-2-methylisoquinolin-1-one 183

4-[2-(cis-4-aminocyclohexyl)oxy-5- methylsulfonylphenyl]-2-methylisoquinolin-1-one 184

4-(2-but-2-ynoxy-5-methylsulfonylphenyl)-2- methylisoquinolin-1-one 185

4-(2-but-2-ynoxy-5-ethylsulfonylphenyl)-2- methylisoquinolin-1-one 186

6-fluoro-4-[2-(trans-4-hydroxycyclohexyl)oxy- 5-methylsulfonylphenyl]-2-methylisoquinolin-1-one 187

7-fluoro-4-[2-(trans-4-hydroxycyclohexyl)oxy- 5-methylsulfonylphenyl]-2-methylisoquinolin-1-one 188

4-[5-ethylsulfonyl-2-(trans-4- hydroxycyclohexyl)oxyphenyl]-6-fluoro-2-methylisoquinolin-1-one 189

4-[5-ethylsulfonyl-2-(trans-4- hydroxycyclohexyl)oxyphenyl]-7-fluoro-2-methylisoquinolin-1-one 190

2-methyl-4-[5-methylsulfonyl-2-(oxolan-3-ylamino)phenyl]isoquinolin-1-one 191

2-methyl-4-[5-methylsulfonyl-2-(oxan-4- ylamino)phenyl]isoquinolin-1-one192

4-[2-[(trans-4-hydroxycyclohexyl)amino]-5- methylsulfonylphenyl]-2-methylisoquinolin-1-one 193

4-[2-(cyclopropylmethylamino)-5- ethylsulfonylphenyl]-2-methylisoquinolin-1-one 194

4-[2-(cyclopropylmethylamino)-5- methylsulfonylphenyl]-2-methylisoquinolin-1-one 195

4-[2-(cyclopropylmethylamino)-5- ethylsulfonylphenyl]-7-fluoro-2-methylisoquinolin-1-one 196

4-[2-(cyclopropylmethylamino)-5- methylsulfonylphenyl]-7-fluoro-2-methylisoquinolin-1-one 197

4-[2-(cyclopropylmethoxy)-5- methylsulfonylphenyl]-2-methyl-6-(trifluoromethyl)isoquinolin-1-one 198

4-[2-(cyclopropylmethoxy)-5- methylsulfonylphenyl]-6-methoxy-2-methylisoquinolin-1-one 199

4-[3-(cyclopropylmethoxy)-6- methylsulfonylpyridin-2-yl]-2-methylisoquinolin-1-one 200

4-[5-(cyclopropylmethoxy)-2- methylsulfonylpyridin-4-yl]-2-methylisoquinolin-1-one 201

4-[3-(cyclopropylmethoxy)-6- methylsulfonylpyridin-2-yl]-7-fluoro-2-methylisoquinolin-1-one 202

4-[3-(cyclopropylmethoxy)-6- methylsulfonylpyridin-2-yl]-6-fluoro-2-methylisoquinolin-1-one 203

4-[5-(cyclopropylmethoxy)-2- methylsulfonylpyridin-4-yl]-7-fluoro-2-methylisoquinolin-1-one 204

4-(2-ethoxy-5-ethylsulfonylthiophen-3-yl)-2- methylisoquinolin-1-one 205

4-[2-(cyclopropylmethylamino)-5- ethylsulfonylthiophen-3-yl]-2-methylisoquinolin-1-one 206

4-[3-(cyclopropylmethoxy)-6- ethylsulfonylpyridin-2-yl]-2-methylisoquinolin-1-one 207

4-[5-(cyclopropylmethoxy)-2- ethylsulfonylpyridin-4-yl]-2-methylisoquinolin-1-one 208

4-[5-(2-hydroxyethylsulfonyl)-2-methoxyphenyl]-2-methyl-6-(1-methylpyrazol- 4-yl)isoquinolin-1-one 209

N-[4-(cyclopropylmethoxy)-2-fluoro-5-[2-methyl-6-(1-methylpyrazol-4-yl)-1-oxoisoquinolin-4-yl]phenyl]ethanesulfonamide 210

4-(5-ethylsulfonyl-2-methoxyphenyl)-2-methyl-6-(1H-pyrazol-4-yl)isoquinolin-1-one 211

4-(2-ethoxy-5-methylsulfonylphenyl)-2- methyl-6-(1-methylpyrazol-4-yl)isoquinolin-1-one 212

2-methyl-6-(1-methylpyrazol-4-yl)-4-(5- methylsulfonyl-2-propoxyphenyl)isoquinolin-1-one 213

N-[2-[2-methyl-6-(1-methylpyrazol-4-yl)-1-oxoisoquinolin-4-yl]pyridin-4-yl] ethanesulfonamide 214

[4-(cyclopropylmethoxy)-3-(2-methyl-1-oxoisoquinolin-4-yl)phenyl]sulfamate 215

[4-(cyclopropylmethoxy)-3-(1,5-dimethyl-6-oxopyridin-3-yl)phenyl]sulfamate 216

4-(2-ethoxy-5-methylsulfonylphenyl)-2-methyl-5,6,7,8-tetrahydro-isoquinolin-1-one 217

4-[2-(cyclopropylmethoxy)-5- methylsulfonylphenyl]-2-methyl-5,6,7,8-tetrahydroisoquinolin-1-one 218

N-[4-(cyclopropylmethoxy)-2-fluoro-5-(2-methyl-1-oxo-5,6,7,8-tetrahydroisoquinolin-4-yl)phenyl]methanesulfonamide 219

4-[2-(cyclopropylmethoxy)-5- ethylsulfonylphenyl]-2-methyl-5,6,7,8-tetrahydroisoquinolin-1-one 220

N-[2-(2-methyl-1-oxoisoquinolin-4-yl)-4- methylsulfonylphenyl]-cyclopropanecarboxamide 221

N-[2-(2-methyl-1-oxoisoquinolin-4-yl)-4-methylsulfonylphenyl]propanamide 222

N-[2-(2-methyl-1-oxoisoquinolin-4-yl)-4- methylsulfonylphenyl]acetamide223

4-[2-(cyclopropylmethylamino)-5- methylsulfonylphenyl]-2-methyl-5,6,7,8-tetrahydroisoquinolin-1-one 224

8-[2-(cyclopropylmethoxy)-5- methylsulfonylphenyl]-6-methyl-2-(1-methylpyrazol-4-yl)pyrido[4,3-d] pyrimidin-5-one 225

8-(5-ethylsulfonyl-2-propoxyphenyl)-6-methyl-2-(1-methylpyrazol-4-yl)pyrido[4,3-d] pyrimidin-5-one 226

8-[2-(cyclopropylmethoxy)-5- ethylsulfonylphenyl]-6-methyl-2-(1-methylpyrazol-4-yl)pyrido[4,3-d] pyrimidin-5-one 227

8-(2-ethoxy-5-ethylsulfonylphenyl)-6-methyl-2-(1-methylpyrazol-4-yl)pyrido[4,3-d] pyrimidin-5-one 228

6-methyl-2-(1-methylpyrazol-4-yl)-8-(5-methylsulfonyl-2-propoxyphenyl)pyrido[4,3-d] pyrimidin-5-one 229

N-[4-(2,4-difluorophenoxy)-3-(1,5-dimethyl-6- oxopyridin-3-yl)phenyl]-N-methylmethanesulfonamide 230

N-[4-(2,4-difluorophenoxy)-3-(1,5-dimethyl-6-oxopyridin-3-yl)phenyl]-N-(oxetan-3-yl) methanesulfonamide 231

8-[2-(cyclopropylmethoxy)-5- methylsulfonylphenyl]-6-methylpyrido[4,3-d]pyrimidin-5-one 232

8-[2-(cyclopropylmethoxy)-5-ethyl- sulfonylphenyl]-6-methylpyrido[4,3-d]pyrimidin-5-one 233

8-[2-(2,4-difluorophenoxy)-5-methylsulfonylphenyl]-6-methylpyrido[4,3-d] pyrimidin-5-one 234

8-[2-(2,4-difluorophenoxy)-5- ethylsulfonylphenyl]-6-methylpyrido[4,3-d]pyrimidin-5-one 235

5-[2-(cyclopropylmethoxy)-5- methylsulfonylphenyl]-7-methyl-[1,2,4]triazolo[4,3-a]pyrazin-8-one 236

N-[4-(2,4-difluorophenoxy)-3-(7-methyl-8-oxo-[1,2,4]triazolo[4,3-a]pyrazin-5-yl) phenyl]ethanesulfonamide 237

7-[2-(cyclopropylmethoxy)-5- methylsulfonylphenyl]-5-methyl-[1,3]oxazolo[4,5-c]pyridin-4-one 238

7-[2-(cyclopropylmethoxy)-5- methylsulfonylphenyl]-2,5-dimethyl-[1,3]oxazolo[4,5-c]pyridin-4-one 239

5-methyl-7-[5-(methylsulfonylmethyl)-2- (2,2,2-trifluoroethoxy)phenyl]-[1,3]oxazolo[4,5-c]pyridin-4-one 240

N-[4-(2,4-difluorophenoxy)-3-(5-methyl-4-oxo-[1,3]oxazolo[4,5-c]pyridin-7-yl) phenyl]ethanesulfonamide 241

N-[4-(2,4-difluorophenoxy)-3-(2,5-dimethyl-4-oxo-[1,3]oxazolo-[4,5-c]pyridin-7-yl)phenyl] ethanesulfonamide 242

5-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-1-(cyclopropyl-methyl)- 3-methylpyridin-2-one 243

5-[2-(cyclopropylmethoxy)-5- methylsulfonylphenyl]-3-methyl-1-(2-methylpropyl)pyridin-2-one 244

5-[2-(cyclopropylmethoxy)-5- methylsulfonylphenyl]-1-(2-methoxyethyl)-3-methylpyridin-2-one 245

5-[2-(cyclopropylmethoxy)-5- methylsulfonylphenyl]-3-methyl-1-(oxetan-3-ylmethyl)pyridin-2-one 246

5-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-3-methyl-1-(1,3-oxazol- 4-ylmethyl)pyridin-2-one247

N-[3-[1-(cyclopropylmethyl)-5-methyl-6-oxopyridin-3-yl]-4-(2,4-difluorophenoxy) phenyl]ethanesulfonamide 248

N-[4-[1-(cyclopropylmethyl)-5-methyl-6-oxopyridin-3-yl]-5-(2,4-difluorophenoxy)pyrimidin-2-yl]methanesulfonamide 249

N-[4-[1-(cyclopropylmethyl)-5-methyl-6-oxopyridin-3-yl]-5-(2,4-difluorophenoxy)pyrimidin-2-yl]ethanesulfonamide 250

1-(cyclopropylmethyl)-5-[4-(2,4-difluoro-phenoxy)-1-(methylsulfonyl-methyl)-6-oxopyridin-3-yl]-3-methylpyridin-2-one 251

1-cyclopropyl-5-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-3-methyl-pyridin-2-one 252

4-[2-(cyclopropylmethoxy)-5-ethyl-sulfonylphenyl]-6-methylfuro[2,3-c]pyridin- 7-one 253

N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7- oxofuro[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamide 254

4-[2-(cyclopropylmethoxy)-5-methyl-sulfonylphenyl]-6-methylfuro[2,3-c]pyridin- 7-one 255

N-[4-(cyclopropylmethoxy)-3-(6-methyl-7-oxofuro[2,3-c]pyridin-4-yl)phenyl] ethanesulfonamide 256

N-[6-(2,4-difluorophenoxy)-5-(6-methyl-7-oxofuro[2,3-c]pyridin-4-yl)pyridin-3-yl] ethanesulfonamide 257

N-[6-(cyclopropylmethoxy)-5-(6-methyl-7-oxofuro[2,3-c]pyridin-4-yl)pyridin-3-yl] ethanesulfonamide 258

6-methyl-4-[5-(methylsulfonylmethyl)-2-(2,2,2-trifluoroethoxy)phenyl]furo[2,3- c]pyridin-7-one 259

4-[3-(cyclopropylmethoxy)-6- methylsulfonylpyridin-2-yl]-6-methylfuro[2,3-c]pyridin-7-one 260

2-chloro-4-[2-(cyclopropylmethoxy)-5- methylsulfonylphenyl]-6-methylfuro[2,3-c]pyridin-7-one 261

N-[6-(cyclopropylmethoxy)-5-(2-fluoro-6-methyl-7-oxofuro[2,3-c]pyridin-4-yl)pyridin- 3-yl]ethanesulfonamide 262

N-[5-(2,4-difluorophenoxy)-4-(6-methyl-7-oxofuro[2,3-c]pyridin-4-yl)pyrimidin-2-yl] methanesulfonamide 263

N-[5-(2,4-difluorophenoxy)-4-(6-methyl-7-oxofuro[2,3-c]pyridin-4-yl)pyrimidin-2-yl] ethanesulfonamide 264

N-[5-(cyclopropylmethoxy)-4-(6-methyl-7-oxofuro[2,3-c]pyridin-4-yl)pyrimidin-2-yl] ethanesulfonamide 265

4-[2-(cyclopropylmethoxy)-5- ethylsulfonylphenyl]-6-methyl-7-oxothieno[2,3-c]pyridine-2-carboxamide 266

4-[2-(cyclopropylmethoxy)-5- (ethylsulfonylamino)phenyl]-6-methyl-7-oxothieno[2,3-c]pyridine-2-carboxamide 267

4-[2-(cyclopropylmethoxy)-5- methylsulfonylphenyl]-6-methyl-7-oxothieno[2,3-c]pyridine-2-carboxamide 268

4-[2-(cyclopropylmethoxy)-5-(ethylsulfonylamino)pyridin-3-yl]-6-methyl-7-oxothieno[2,3-c]pyridine-2-carboxamide 269

N-[4-(2,4-difluorophenoxy)-3-(2,6-dimethyl-7-oxofuro[2,3-c]pyridin-4-yl) phenyl]ethanesulfonamide 270

4-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-2,6-dimethylfuro[2,3-c] pyridin-7-one 271

N-[4-(2,4-difluorophenoxy)-3-(5-fluoro-1- methyl-6-oxopyridin-3-yl)phenyl]methanesulfonamide 272

3-chloro-5-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-1-methyl-pyridin-2-one 273

5-[5-(2,4-difluorophenoxy)-2- methylsulfonylpyrimidin-4-yl]-1-methyl-3-propan-2-ylpyridin-2-one 274

5-[2-(cyclopropylmethoxy)-5- ethylsulfonylphenyl]-3-fluoro-1-methylpyridin-2-one 275

3-chloro-5-[2-(cyclopropylmethylamino)-5-ethylsulfonylphenyl]-1-methyl-pyridine-2-one 276

5-[2-(2,4-difluorophenoxy)-5- (methanesulfonylmethyl)phenyl]-3-(²H₃)methyl-1-methyl-1,2-dihydro- pyridin-2-one 277

N-[4-(2,4-difluorophenoxy)-3-[5-(²H₃)methyl-1-methyl-6-oxo-1,6-dihydropyridin-3-yl] phenyl]methanesulfonamide 278

N-[4-(2,4-difluorophenoxy)-3-[5-(²H₃)methyl-1-methyl-6-oxo-1,6-dihydropyridin-3- yl]phenyl]ethane-1-sulfonamide 279

N-[3-(5-cyclopropyl-1-methyl-6-oxopyridin-3-yl)-4-(2,4-difluoro-phenoxy)phenyl] methanesulfonamide 280

3-cyclopropyl-5-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-1-methylpyridin-2-one 281

N-[4-(2,4-difluorophenoxy)-3-(1-methyl-6-oxo-5-pyrrolidin-1-ylpyridin-3-yl) phenyl]methanesulfonamide 282

5-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-1-methyl-3-pyrrolidin-1- ylpyridin-2-one 283

N-[4-(2,4-difluorophenoxy)-3-(5-ethynyl-1- methyl-6-oxopyridin-3-yl)phenyl]ethanesulfonamide 284

5-[2-(cyclopropylmethoxy)-5- ethylsulfonylphenyl]-3-ethynyl-1-methylpyridin-2-one 285

5-[2-(cyclopropylmethoxy)-5- methylsulfonylphenyl]-3-ethynyl-1-methylpyridin-2-one 286

N-[4-(2,4-difluorophenoxy)-3-(5-ethynyl-1- methyl-6-oxopyridin-3-yl)phenyl]methanesulfonamide 287

5-[2-(cyclopropylmethoxy)-5- ethylsulfonylphenyl]-3-(difluoromethoxy)-1-methylpyridin-2-one 288

5-[2-(cyclopropylmethoxy)-5- ethylsulfonylphenyl]-1-methyl-3-(2,2,2-trifluoroethoxy)pyridin-2-one 289

N-[3-[5-(difluoromethoxy)-1-methyl-6-oxopyridin-3-yl]-4-(2,4-difluorophenoxy) phenyl]ethanesulfonamide 290

N-[4-(2,4-difluorophenoxy)-3-[1-methyl-6-oxo-5-(2,2,2-trifluoroethoxy)pyridin-3-yl] phenyl]ethanesulfonamide 291

3-(difluoromethoxy)-5-[2-(2,4- difluorophenoxy)-5-(ethylsulfonylmethyl)phenyl]-1- methylpyridin-2-one 292

5-[2-(2,4-difluorophenoxy)-5- (ethylsulfonylmethyl)phenyl]-1-methyl-3-(2,2,2-trifluoroethoxy)pyridin-2-one 293

5-[2-(cyclopropylmethoxy)-5- methylsulfonylphenyl]-1-methyl-3-(1-methylpyrazol-4-yl)oxypyridin-2-one 294

5-[2-(cyclopropylmethoxy)-5- methylsulfonylphenyl]-1-methyl-3-(1-propan-2-ylpyrazol-4-yl)oxypyridin-2-one 295

5-[2-(cyclopropylmethoxy)-5- methylsulfonylphenyl]-1-methyl-3-phenoxypyridin-2-one 296

N-[4-(1-butyl-5-methyl-6-oxopyridin-3-yl)-5-(2,4-difluorophenoxy)pyrimidin-2-yl] methanesulfonamide 297

N-[4-(1-butyl-5-methyl-6-oxopyridin-3-yl)-5-(2,4-difluorophenoxy)pyrimidin-2-yl] ethanesulfonamide 298

N-[4-[1-(cyclobutylmethyl)-5-methyl-6- oxopyridin-3-yl]-5-(2,4-difluorophenoxy)pyrimidin-2-yl] methanesulfonamide 299

N-[4-[1-(cyclobutylmethyl)-5-methyl-6- oxopyridin-3-yl]-5-(2,4-difluorophenoxy)pyrimidin-2-yl] ethanesulfonamide 300

N-[5-ethyl-4-(2-methyl-1-oxoisoquinolin-4-yl)pyrimidin-2-yl]ethanesulfonamide 301

2-methyl-4-(2-methylsulfonyl-5- propylpyrimidin-4-yl)isoquinolin-1-one302

5-(5-ethyl-2-methylsulfonylpyrimidin-4-yl)- 1,3-dimethylpyridin-2-one303

1,3-dimethyl-5-(2-methylsulfonyl-5- propylpyrimidin-4-yl)pyridin-2-one304

4-(5-butyl-2-methylsulfonylpyrimidin-4-yl)-2- methylisoquinolin-1-one305

5-(5-butyl-2-methylsulfonylpyrimidin-4-yl)- 1,3-dimethylpyridin-2-one306

N-[4-(2-methyl-1-oxoisoquinolin-4-yl)-5-propylpyrimidin-2-yl]ethanesulfonamide 307

N-[4-(1,5-dimethyl-6-oxopyridin-3-yl)-5-ethylpyrimidin-2-yl]ethanesulfonamide 308

N-[4-(1,5-dimethyl-6-oxopyridin-3-yl)-5-propylpyrimidin-2-yl]ethanesulfonamide 309

N-[5-butyl-4-(2-methyl-1-oxoisoquinolin-4-yl)pyrimidin-2-yl]ethanesulfonamide 310

N-[5-butyl-4-(1,5-dimethyl-6-oxopyridin-3-yl)pyrimidin-2-yl]ethanesulfonamide 311

4-[5-(cyclopropylmethoxy)-2- methylsulfonylpyrimidin-4-yl]-2-methylisoquinolin-1-one 312

5-(2-ethyl-5-methylsulfonylphenyl)-1- methylpyridin-2-one 313

1-methyl-5-(5-methylsulfonyl-2- propylphenyl)pyridin-2-one 314

2-methyl-4-(5-methylsulfonyl-2- propylphenyl)isoquinolin-1-one 315

5-[2-(2-cyclopropylethyl)-5- methylsulfonylphenyl]-1-methylpyridin-2-one 316

4-(2-ethyl-5-methylsulfonylphenyl)-2- methylisoquinolin-1-one 317

5-(2-butyl-5-methylsulfonylphenyl)-1- methylpyridin-2-one 318

4-(2-butyl-5-methylsulfonylphenyl)-2- methylisoquinolin-1-one 319

4-[2-(2-cyclopropylethyl)-5- methylsulfonylphenyl]-2-methylisoquinolin-1-one 320

N-[6-(cyclopropylmethoxy)-5-(2-methyl-1-oxoisoquinolin-4-yl)pyridin-3-yl] ethanesulfonamide 321

4-[2-(cyclopropylmethoxy)-5- methylsulfonylpyridin-3-yl]-2-methylisoquinolin-1-one 322

4-[2-(cyclopropylmethoxy)-5- ethylsulfonylpyridin-3-yl]-2-methylisoquinolin-1-one 323

5-[3-[(4-methoxyphenyl)methoxy]-5- methylsulfonylphenyl]-1,3-dimethylpyridin-2-one 324

1,3-dimethyl-5-(3-methylsulfonyl-5- phenylmethoxyphenyl)pyridin-2-one325

5-[3-(cyclopropylmethoxy)-5- methylsulfonylphenyl]-1,3-dimethylpyridin-2-one 326

1,3-dimethyl-5-[3-methylsulfonyl-5-(2- phenylethoxy)phenyl]pyridin-2-one327

5-[3-(2-cyclopropylethoxy)-5- methylsulfonylphenyl]-1,3-dimethylpyridin-2-one 328

1,3-dimethyl-5-[3-methylsulfonyl-5-(2,2,2-trifluoroethoxy)phenyl]pyridin-2-one 329

1,3-dimethyl-5-[3-[(3-methyloxetan-3-yl)methoxy]-5-methylsulfonylphenyl] pyridine-2-one 330

1,3-dimethyl-5-[3-methylsulfonyl-5-(pyridin-2-ylmethoxy)phenyl]pyridin-2-one 331

5-[3-[(2,6-dimethylphenyl)methoxy]-5- methylsulfonylphenyl]-1,3-dimethylpyridin-2-one 332

5-[3-[(2-chlorophenyl)methoxy]-5- methylsulfonylphenyl]-1,3-dimethylpyridin-2-one 333

5-[3-[[2-(difluoromethoxy)phenyl]methoxy]-5- methylsulfonylphenyl]-1,3-dimethylpyridin-2-one 334

2-[[3-(1,5-dimethyl-6-oxopyridin-3-yl)-5-methylsulfonylphenoxy]methyl]benzonitrile 335

5-[3-[(2,4-difluorophenyl)methoxy]-5- methylsulfonylphenyl]-1,3-dimethylpyridin-2-one 336

1,3-dimethyl-5-[3-methylsulfonyl-5-(1- phenylethoxy)phenyl]pyridin-2-one337

5-[3-[(2,3-dichlorophenyl)methoxy]-5- methylsulfonylphenyl]-1,3-dimethylpyridin-2-one 338

1,3-dimethyl-5-[3-methylsulfonyl-5-(pyridin-3-ylmethoxy)phenyl]pyridin-2-one 339

3-[[3-(1,5-dimethyl-6-oxopyridin-3-yl)-5-methylsulfonylphenoxy]methyl]benzonitrile 340

5-(3-but-2-ynoxy-5-methylsulfonylphenyl)-1,3- dimethylpyridin-2-one 341

1,3-dimethyl-5-[3-methylsulfonyl-5-(1- phenylethoxy)phenyl]pyridin-2-one342

N-[3-(2,4-difluorophenoxy)-5-(1,5-dimethyl-6-oxopyridin-3-yl)phenyl]ethanesulfonamide 343

4-[3-[(4-methoxyphenyl)methoxy]-5- methylsulfonylphenyl]-2-methylisoquinolin-1-one 344

2-methyl-4-(3-methylsulfonyl-5- phenylmethoxyphenyl)isoquinolin-1-one345

4-[3-(cyclopropylmethoxy)-5- methylsulfonylphenyl]-2-methylisoquinolin-1-one 346

N-[4-(2,4-difluorophenoxy)-6-(1,5-dimethyl-6-oxopyridin-3-yl)pyrimidin-2-yl] ethanesulfonamide 347

N-[2-(2,4-difluorophenoxy)-6-(1,5-dimethyl-6-oxopyridin-3-yl)pyrimidin-4-yl] ethanesulfonamide 348

4-[3-[[2-(difluoromethoxy)phenyl]methoxy]-5-methylsulfonylphenyl]-6-methylfuro[2,3-c] pyridin-7-one 349

6-methyl-4-(3-methylsulfonyl-5- phenylmethoxyphenyl)furo[2,3-c]pyridin-7-one 350

4-[3-(cyclopropylmethoxy)-5- methylsulfonylphenyl]-6-methylfuro[2,3-c]pyridin-7-one 351

1-methyl-5-(2-methylsulfonyl-5- propylpyrimidin-4-yl)pyridin-2-one 352

5-(5-butyl-2-methylsulfonylpyrimidin-4-yl)-1- methylpyridin-2-one 353

3-chloro-1-methyl-5-(2-methylsulfonyl-5-propylpyrimidin-4-yl)pyridin-2-one 354

5-(5-butyl-2-methylsulfonylpyrimidin-4-yl)-3-chloro-1-methylpyridin-2-one 355

3-methoxy-1-methyl-5-(2-methylsulfonyl-5-propylpyrimidin-4-yl)pyridin-2-one 356

5-(5-butyl-2-methylsulfonylpyrimidin-4-yl)-3-methoxy-1-methylpyridin-2-one 357

N-[4-(1-methyl-6-oxopyridin-3-yl)-5-propylpyrimidin-2-yl]ethanesulfonamide 358

N-[5-butyl-4-(1-methyl-6-oxopyridin-3-yl)pyrimidin-2-yl]ethanesulfonamide 359

N-[4-(5-chloro-1-methyl-6-oxopyridin-3-yl)-5-propylpyrimidin-2-yl]ethanesulfonamide 360

N-[5-butyl-4-(5-chloro-1-methyl-6-oxopyridin-3-yl)pyrimidin-2-yl]ethanesulfonamide 361

N-[4-(5-methoxy-1-methyl-6-oxopyridin-3-yl)-5-propylpyrimidin-2-yl]ethanesulfonamide 362

N-[5-butyl-4-(5-methoxy-1-methyl-6- oxopyridin-3-yl)pyrimidin-2-yl]ethanesulfonamide 363

N-[5-butyl-4-(1,5-dimethyl-6-oxopyridin-3-yl)pyrimidin-2-yl]methanesulfonamide 364

4-[2-(cyclopropylmethoxy)-5-propan-2-ylsulfonylphenyl]-2-methylisoquinolin-1-one 365

8-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-6-methyl-4H-pyrido[4,3- b][1,4]oxazine-3,5-dione366

8-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-6-methyl-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-5-one 367

N-[4-(2,4-difluorophenoxy)-3-(7-methyl-8- oxoimidazo[1,5-a]pyrazin-5-yl)phenyl]methanesulfonamide 368

5-[2-(cyclopropylmethoxy)-5- ethylsulfonylphenyl]-7-methylimidazo[1,5-a]pyrazin-8-one 369

5-[2-(2,4-difluorophenoxy)-5- (ethylsulfonylmethyl)phenyl]-7-methylimidazo[1,5-a]pyrazin-8-one 370

7-methyl-5-[5-(methylsulfonylmethyl)-2-(2,2,2-trifluoroethoxy)phenyl]imidazo[1,5-a] pyrazin-8-one 371

5-[5-(ethylsulfonylmethyl)-2-(2,2,2- trifluoroethoxy)phenyl]-7-methylimidazo[1,5-a]pyrazin-8-one 372

5-[2-(2,4-difluorophenoxy)-5- (methylsulfonylmethyl)phenyl]-7-methylimidazo[1,5-a]pyrazin-8-one 373

5-[2-(4,4-difluorocyclohexyl)oxy-5-ethylsulfonylphenyl]-7-methylimidazo[1,5-a] pyrazin-8-one 374

5-(2-cyclopentyloxy-5-ethylsulfonylphenyl)-7-methylimidazo[1,5-a]pyrazin-8-one 375

5-[2-(cyclopropylmethylamino)-5-ethylsulfonylphenyl]-7-methylimidazo[1,5- a]pyrazin-8-one 376

5-[2-(2,4-difluorophenoxy)-5-ethylsulfonylphenyl]-7-methylimidazo[1,5-a] pyrazin-8-one 377

7-[2-(cyclopropylmethoxy)-5- methylsulfonylphenyl]-5-methylfuro[3,2-c]pyridin-4-one 378

7-[2-(cyclopropylmethoxy)-5- ethylsulfonylphenyl]-5-methylfuro[3,2-c]pyridin-4-one 379

N-[4-(2,4-difluorophenoxy)-3-(5-methyl-4- oxofuro[3,2-c]pyridin-7-yl)phenyl]ethanesulfonamide 380

N-[4-(2,4-difluorophenoxy)-3-(5-methyl-4- oxofuro[3,2-c]pyridin-7-yl)phenyl]methanesulfonamide 381

4-(cyclopropylmethoxy)-5-(1-methyl-6- oxopyridin-3-yl)-1-(methylsulfonylmethyl)pyridin-2-one 382

5-[4-(cyclopropylmethoxy)-1- (methylsulfonylmethyl)-6-oxopyridin-3-yl]-1,3-dimethylpyridin-2-one 383

4-[4-(cyclopropylmethoxy)-1-(methylsulfonylmethyl)-6-oxopyridin-3-yl]-7-fluoro-2-methylisoquinolin-1-one 384

4-[4-(cyclopropylmethoxy)-1-(methylsulfonylmethyl)-6-oxopyridin-3-yl]-2- methylisoquinolin-1-one 385

5-[4-(2,4-difluorophenoxy)-1- (methylsulfonylmethyl)-6-oxopyridin-3-yl]-1,3-dimethylpyridin-2-one 386

4-(2,4-difluorophenoxy)-5-(1-methyl-6- oxopyridin-3-yl)-1-(methylsulfonylmethyl)pyridin-2-one 387

4-[4-(2,4-difluorophenoxy)-1-(methylsulfonylmethyl)-6-oxopyridin-3-yl]-2- methylisoquinolin-1-one 388

5-(2-but-2-ynoxy-5-methylsulfonylphenyl)-1,3- dimethylpyridin-2-one 389

5-(2-but-2-ynoxy-5-ethylsulfonylphenyl)-3- methoxy-1-methylpyridin-2-one390

5-(5-ethylsulfonyl-2-pent-2-ynoxyphenyl)-3-methoxy-1-methylpyridin-2-one 391

5-[2-(3-cyclopropylprop-2-ynoxy)-5- ethylsulfonylphenyl]-3-methoxy-1-methylpyridin-2-one 392

5-[2-(2,4-difluorophenoxy)-5- ethylsulfonylphenyl]-1-methyl-3-(trifluoromethyl)pyridin-2-one 393

4-[2-(cyclopropylmethoxy)-5-propan-2- ylsulfonylphenyl]-6-methoxy-2-methylisoquinolin-1-one 394

5-[2-(cyclopropylmethoxy)-5-propan-2-ylsulfonylphenyl]-1,3-dimethylpyridin-2-one 395

N-[3-(1,5-dimethyl-6-oxopyridin-3-yl)-5-phenylmethoxyphenyl]ethanesulfonamide 396

5-[2-(2,4-difluoroanilino)-5- ethylsulfonylphenyl]-1,3-dimethylpyridin-2-one 397

5-[2-[(4,4-difluorocyclohexyl)amino]-5-ethylsulfonylphenyl]-1,3-dimethylpyridin- 2-one 398

5-[2-(2,4-difluoroanilino)-5- methylsulfonylphenyl]-1,3-dimethylpyridin-2-one 399

5-[2-(cyclopropylmethoxy)-5- ethylsulfonylphenyl]-3-methoxy-1-methylpyridin-2-one 400

5-[2-(2,4-difluorophenoxy)-5- (methylsulfonylmethyl)phenyl]-3-methoxy-1-methylpyridin-2-one 401

5-[2-(trans-4-hydroxycyclohexyl)oxy-5-methylsulfonylphenyl]-1,3-dimethylpyridin- 2-one 402

N-[4-(2,4-difluorophenoxy)-3-(1-methyl-5-methylsulfanyl-6-oxopyridin-3-yl) phenyl]ethanesulfonamide 403

5-[2-(cis-4-aminocyclohexyl)oxy-5- methylsulfonylphenyl]-1,3-dimethylpyridin-2-one 404

5-[2-(trans-4-aminocyclohexyl)oxy-5- methylsulfonylphenyl]-1,3-dimethylpyridin-2-one 405

1,3-dimethyl-5-[5-methylsulfonyl-2-(3,3,3-trifluoropropoxy)phenyl]pyridin-2-one 406

5-[2-(2,4-difluorophenoxy)-5- (methylsulfonylmethyl)phenyl]-1-(2-hydroxyethyl)-3-methylpyridin-2-one 407

5-[5-(ethylsulfonylmethyl)-2-(2,2,2-trifluoroethoxy)phenyl]-1-(2-hydroxyethyl)- 3-methylpyridin-2-one 408

5-[2-(cyclopropylmethylamino)-5- ethylsulfonylphenyl]-1-methyl-3-(methylamino)pyridin-2-one 409

5-[2-(cyclopropylmethoxy)-5- ethylsulfonylphenyl]-1-methyl-3-(methylamino)pyridin-2-one 410

N-[4-(2,4-difluorophenoxy)-3-[1-methyl-5-(methylamino)-6-oxopyridin-3-yl] phenyl]ethanesulfonamide 411

5-[5-(ethylsulfonylmethyl)-2-(2,2,2- trifluoroethoxy)phenyl]-1,3-dimethylpyridin-2-one 412

N-[4-(2,4-difluorophenoxy)-3-[1-methyl-5-(methylamino)-6-oxopyridin-3-yl] phenyl]methanesulfonamide 413

5-[2-[(4,4-difluorocyclohexyl)amino]-5- methylsulfonylphenyl]-1,3-dimethylpyridin-2-one 414

5-[2-(cyclopropylmethylamino)-5- ethylsulfonylphenyl]-3-methoxy-1-methylpyridin-2-one 415

5-[2-(4,4-difluorocyclohexyl)oxy-5- methylsulfonylphenyl]-1,3-dimethylpyridin-2-one 416

5-[2-(cyclopentylamino)-5- ethylsulfonylphenyl]-1,3-dimethylpyridin-2-one 417

5-[2-(cyclopentylamino)-5- methylsulfonylphenyl]-1,3-dimethylpyridin-2-one 418

3-chloro-1-methyl-5-[5- (methylsulfonylmethyl)-2-(2,2,2-trifluoroethoxy)phenyl]pyridin-2-one 419

5-(2-cyclopentyloxy-5-methylsulfonylphenyl)- 1,3-dimethylpyridin-2-one420

1,3-dimethyl-5-[5-methylsulfonyl-2-(oxan-4- yloxy)phenyl]pyridin-2-one421

3-fluoro-1-methyl-5-[5- (methylsulfonylmethyl)-2-(2,2,2-trifluoroethoxy)phenyl]pyridin-2-one 422

5-[2-(cyclopropylmethylamino)-5- methylsulfonylphenyl]-1,4-dimethylpyridin-2-one 423

5-[2-(cyclopropylmethylamino)-5- ethylsulfonylphenyl]-1,4-dimethylpyridin-2-one 424

N-[4-(1-methyl-6-oxopyridin-3-yl)-5-phenylthiophen-2-yl]ethanesulfonamide 425

1,3-dimethyl-5-[5-methylsulfonyl-2-(oxolan-3-ylamino)phenyl]pyridin-2-one 426

1,3-dimethyl-5-[5-methylsulfonyl-2-(oxolan- 3-yloxy)phenyl]pyridin-2-one427

1,3-dimethyl-5-[5-(methylsulfonylmethyl)-2-(2,2,2-trifluoroethoxy)phenyl]pyridin-2-one 428

5-[2-(cyclopropylmethylamino)-5- methylsulfonylphenyl]-1-ethyl-3-methylpyridin-2-one 429

5-[2-(2,4-difluorophenoxy)-5- (methylsulfonylmethyl)phenyl]-1-ethyl-3-methylpyridin-2-one 430

N-[3-(1,5-dimethyl-6-oxopyridin-3-yl)-4-(trans-4-hydroxycyclohexyl)oxyphenyl] ethanesulfonamide 431

N-[3-(1,5-dimethyl-6-oxopyridin-3-yl)-4-(cis-4-hydroxycyclohexyl)oxyphenyl] ethanesulfonamide 432

N-[4-(1-methyl-6-oxopyridin-3-yl)-5-(2- methylphenyl)thiophen-2-yl]ethanesulfonamide 433

N-[3-(1,5-dimethyl-6-oxopyridin-3-yl)-4-(trans-4-hydroxycyclohexyl)oxyphenyl] methanesulfonamide 434

N-[3-(1,5-dimethyl-6-oxopyridin-3-yl)-4-(cis-4-hydroxycyclohexyl)oxyphenyl] methanesulfonamide 435

N-[5-(2-ethylphenyl)-4-(1-methyl-6- oxopyridin-3-yl)thiophen-2-yl]ethanesulfonamide 436

1,3-dimethyl-5-[5-methylsulfonyl-2-(oxan-4- ylamino)phenyl]pyridin-2-one437

5-[2-(2,4-difluorophenoxy)-5- (methylsulfonylmethyl)phenyl]-3-fluoro-1-methylpyridin-2-one 438

5-[2-(cyclopropylmethylamino)-5-methylsulfonylphenyl]-3-(dimethylamino)- 1-methylpyridin-2-one 439

N-[3-(1,5-dimethyl-6-oxopyridin-3-yl)-4-(oxan-4-yloxy)phenyl]methanesulfonamide 440

5-[2-(cyclopropylmethylamino)-5-ethylsulfonylphenyl]-3-(dimethylamino)-1- methylpyridin-2-one 441

N-[3-(1,5-dimethyl-6-oxopyridin-3-yl)-4-(oxan-4-yloxy)phenyl]ethanesulfonamide 442

N-[4-(2,4-difluorophenoxy)-3-(5-methoxy-1- methyl-6-oxopyridin-3-yl)phenyl]methanesulfonamide 443

N-[4-(2,4-difluorophenoxy)-3-(5-methoxy-1- methyl-6-oxopyridin-3-yl)phenyl]ethanesulfonamide 444

N-[3-(1,5-dimethyl-6-oxopyridin-3-yl)-4-(oxolan-3-yloxy)phenyl]methanesulfonamide 445

N-[3-(1,5-dimethyl-6-oxopyridin-3-yl)-4-(oxolan-3-yloxy)phenyl]ethanesulfonamide 446

N-[3-(1,5-dimethyl-6-oxopyridin-3-yl)-4-(oxan-3-yloxy)phenyl]methanesulfonamide 447

N-[4-(4,4-difluorocyclohexyl)oxy-3-(1,5- dimethyl-6-oxopyridin-3-yl)phenyl]methanesulfonamide 448

N-[3-(1,5-dimethyl-6-oxopyridin-3-yl)-4-(oxan-3-yloxy)phenyl]ethanesulfonamide 449

N-[4-(4,4-difluorocyclohexyl)oxy-3-(1,5- dimethyl-6-oxopyridin-3-yl)phenyl]ethanesulfonamide 450

5-[2-(cyclopropylmethoxy)-5- ethylsulfonylphenyl]-1,3-dimethylpyridin-2-one 451

N-[4-(2,4-difluorophenoxy)-3-(5-hydroxy-1- methyl-6-oxopyridin-3-yl)phenyl]ethanesulfonamide 452

4-(cyclopropylmethylamino)-3-(1,5-dimethyl-6-oxopyridin-3-yl)benzenesulfonamide 453

4-(cyclopropylmethylamino)-3-(1-methyl-6-oxopyridin-3-yl)benzenesulfonamide 454

5-[2-(2,4-difluorophenoxy)-5- (methylsulfonylmethyl)phenyl]-1,4-dimethylpyridin-2-one 455

5-[2-(2,4-difluorophenoxy)-5- (methylsulfonylmethyl)phenyl]-1,3-dimethylpyridin-2-one 456

5-(2-ethoxy-5-ethylsulfonylphenyl)-1- (²H₃)methyl-4-methylpyridin-2-one457

5-[2-(cyclopropylmethoxy)-5- ethylsulfonylphenyl]-1-(²H₃)methyl-4-methylpyridin-2-one 458

5-(2-ethoxy-5-ethylsulfonylphenyl)-1,4- dimethylpyridin-2-one 459

5-[2-(cyclobutylmethoxy)-5- methylsulfonylphenyl]-1,3-dimethylpyridin-2-one 460

5-[2-(cyclobutylmethoxy)-5- methylsulfonylphenyl]-1-methylpyridin- 2-one461

5-(5-ethylsulfonyl-2-methoxyphenyl)-3- hydroxy-1-methylpyridin-2-one 462

5-[2-(cyclopropylmethylamino)-5- methylsulfonylphenyl]-1,3-dimethylpyridin-2-one 463

N-[4-(2,4-difluorophenoxy)-3-[5-(dimethylamino)-1-methyl-6-oxopyridin-3- yl]phenyl]methanesulfonamide464

N-[4-(2,4-difluorophenoxy)-3-[5-(dimethylamino)-1-methyl-6-oxopyridin-3- yl]phenyl]ethanesulfonamide 465

5-[2-(cyclopropylmethylamino)-5- ethylsulfonylphenyl]-1,3-dimethylpyridin-2-one 466

5-[2-(cyclopropylmethoxy)-5- ethylsulfonylphenyl]-1,4-dimethylpyridin-2-one 467

N-[3-(5-hydroxy-1-methyl-6-oxopyridin-3-yl) phenyl]methanesulfonamide468

5-[2-(cyclopropylmethylamino)-5- methylsulfonylphenyl]-1-methylpyridin-2-one 469

3-(dimethylamino)-5-(2-ethoxy-5-ethylsulfonylphenyl)-1-methylpyridin-2-one 470

5-[2-(2,4-difluorophenoxy)-5- (methylsulfonylmethyl)phenyl]-1-methylpyridin-2-one 471

N-[3-(1-methyl-6-oxo-5- phenylmethoxypyridin-3-yl)phenyl]methanesulfonamide 472

N-[4-(2,4-difluorophenoxy)-3-(1,5-dimethyl-6-oxopyridin-3-yl)phenyl]ethanesulfonamide 473

5-[2-(cyclopropylmethylamino)-5- ethylsulfonylphenyl]-1-methylpyridin-2-one 474

5-[2-(cyclopropylmethoxy)-5- methylsulfonylphenyl]-3-(dimethylamino)-1-methylpyridin-2-one 475

5-[4-fluoro-2-methoxy-5- (methylsulfonylmethyl)phenyl]-1-methylpyridin-2-one 476

5-[2-(cyclopropylmethoxy)-5- methylsulfonylphenyl]-1,3-dimethylpyridin-2-one 477

5-[2-(cyclopropylmethoxy)-5- methylsulfonylphenyl]-1,4-dimethylpyridin-2-one 478

N-[6-[3-(methanesulfonamido)phenyl]-4-methyl-3-oxopyrazin-2-yl]acetamide 479

N-[3-(1,4-dimethyl-6-oxopyridazin-3- yl)phenyl]ethanesulfonamide 480

N-[3-(1,5-dimethyl-6-oxopyridazin-3-yl) phenyl]ethanesulfonamide 481

N-[5-[3-(methanesulfonamido)phenyl]-1-methyl-2-oxopyridin-3-yl]propanamide 482

N-[5-[3-(methanesulfonamido)phenyl]-1-methyl-2-oxopyridin-3-yl]acetamide 483

1-cyclobutyl-5-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-3-methylpyridin- 2-one 484

N-[3-(1-cyclobutyl-5-methyl-6-oxopyridin-3-yl)-4-(2,4-difluorophenoxy)phenyl] methanesulfonamide 485

1-benzyl-5-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-3-methylpyridin- 2-one 486

1,3-dimethyl-5-(2-methyl-5-methyl-sulfonyl-2,3-dihydro-1-benzofuran-7-yl)pyridin-2-one 487

4-[5-(ethylsulfonylmethyl)-2-(2,2,2- trifluoroethoxy)phenyl]-2-methylisoquinolin-1-one 488

2-methyl-4-[5-(methylsulfonylmethyl)-2- (2,2,2-trifluoroethoxy)phenyl]isoquinolin-1-one 489

1,3-dimethyl-5-(7-methylsulfonyl-2,3-dihydro-1,4-benzodioxin-5-yl)pyridine-2-one 490

N-[2-ethyl-8-(2-methyl-1-oxoisoquinolin-4-yl)-3,4-dihydro-2H-chromen-6-yl] methanesulfonamide 491

N-[2-ethyl-8-(2-methyl-1-oxoisoquinolin-4-yl)-3,4-dihydro-2H-chromen-6-yl] ethanesulfonamide 492

N-[8-(1,5-dimethyl-6-oxopyridin-3-yl)-2-ethyl-3,4-dihydro-2H-chromen-6-yl] ethanesulfonamide 493

4-(2-cyclopropyl-5-methylsulfonyl-2,3- dihydro-1-benzofuran-7-yl)-2-methylisoquinolin-1-one 494

4-(2-ethyl-5-methylsulfonyl-2,3-dihydro-1-benzofuran-7-yl)-2-methylisoquinolin-1-one 495

N-[7-(1,5-dimethyl-6-oxopyridin-3-yl)-2-propyl-2,3-dihydro-1-benzofuran-5-yl] ethanesulfonamide 496

N-[2-cyclopropyl-7-(1,5-dimethyl-6- oxopyridin-3-yl)-2,3-dihydro-1-benzofuran-5-yl]ethanesulfonamide 497

4-[3-(methoxymethyl)-7-methylsulfonyl-2,3-dihydro-1,4-benzodioxin-5-yl]-2- methylisoquinolin-1-one 498

5-[3-(methoxymethyl)-7-methylsulfonyl-2,3-dihydro-1,4-benzodioxin-5-yl]-1,3- dimethylpyridin-2-one 499

4-[3-(methoxymethyl)-7-methylsulfonyl-2,3-dihydro-1,4-benzodioxin-5-yl]-2- methylisoquinolin-1-one 500

5-[3-(methoxymethyl)-7-methylsulfonyl-2,3-dihydro-1,4-benzodioxin-5-yl]-1,3- dimethylpyridin-2-one 501

4-[2-(methoxymethyl)-7-methylsulfonyl-2,3-dihydro-1,4-benzodioxin-5-yl]-2- methylisoquinolin-1-one 502

5-[2-(methoxymethyl)-7-methylsulfonyl-2,3-dihydro-1,4-benzodioxin-5-yl]-1,3- dimethylpyridin-2-one 503

4-[2-(methoxymethyl)-7-methylsulfonyl-2,3-dihydro-1,4-benzodioxin-5-yl]-2- methylisoquinolin-1-one 504

4-[2-(cyclopropylmethoxy)-5- methylsulfonylphenyl]-2-methyl-6,7-dihydro-5H-cyclopenta[c]pyridin-1-one 505

4-[2-(cyclopropylmethoxy)-5- ethylsulfonylphenyl]-2-methyl-6,7-dihydro-5H-cyclopenta[c[pyridin-1-one 506

N-[4-(2,4-difluorophenoxy)-3-(2-methyl-1-oxo-6,7-dihydro-5H-cyclopenta[c]pyridin-4-yl) phenyl]methanesulfonamide507

N-[4-(2,4-difluorophenoxy)-3-(2-methyl-1-oxo-6,7-dihydro-5H-cyclopenta[c]pyridin-4- yl)phenyl]ethanesulfonamide508

5-(5-butyl-2-methylsulfonylpyrimidin-4-yl)-3-methyl-1-propan-2-ylpyridin-2-one 509

N-[5-(2,4-difluorophenoxy)-4-(5-methyl-6-oxo-1-propan-2-ylpyridin-3-yl)pyrimidin-2- yl]ethanesulfonamide 510

5-[5-(2,4-difluorophenoxy)-2- methylsulfonylpyrimidin-4-yl]-3-methyl-1-propan-2-ylpyridin-2-one 511

N-[5-butyl-4-(5-methyl-6-oxo-1-propan-2- ylpyridin-3-yl)pyrimidin-2-yl]ethanesulfonamide 512

N-[5-butyl-4-(1-methyl-6-oxo-5-propan-2- ylpyridin-3-yl)pyrimidin-2-yl]ethanesulfonamide 513

5-(5-butyl-2-methylsulfonylpyrimidin-4-yl)-1-methyl-3-propan-2-ylpyridin-2-one 514

N-[5-(2,4-difluorophenoxy)-4-(1-methyl-6-oxo-5-propan-2-ylpyridin-3-yl)pyrimidin-2- yl]ethanesulfonamide

In some embodiments, the substituted heterocyclic derivative compounddisclosed herein has the structure provided in Table 2.

TABLE 2

Preparation of the Substituted Heterocyclic Derivative Compounds

The compounds used in the reactions described herein are made accordingto organic synthesis techniques known to those skilled in this art,starting from commercially available chemicals and/or from compoundsdescribed in the chemical literature. “Commercially available chemicals”are obtained from standard commercial sources including Acros Organics(Pittsburgh, Pa.), Aldrich Chemical (Milwaukee, Wis., including SigmaChemical and Fluka), Apin Chemicals Ltd. (Milton Park, UK), AvocadoResearch (Lancashire, U.K.), BDH Inc. (Toronto, Canada), Bionet(Cornwall, U.K.), Chemservice Inc. (West Chester, Pa.), CrescentChemical Co. (Hauppauge, N.Y.), Eastman Organic Chemicals, Eastman KodakCompany (Rochester, N.Y.), Fisher Scientific Co. (Pittsburgh, Pa.),Fisons Chemicals (Leicestershire, UK), Frontier Scientific (Logan,Utah), ICN Biomedicals, Inc. (Costa Mesa, Calif.), Key Organics(Cornwall, U.K.), Lancaster Synthesis (Windham, N.H.), MaybridgeChemical Co. Ltd. (Cornwall, U.K.), Parish Chemical Co. (Orem, Utah),Pfaltz & Bauer, Inc. (Waterbury, Conn.), Polyorganix (Houston, Tex.),Pierce Chemical Co. (Rockford, Ill.), Riedel de Haen A G (Hanover,Germany), Spectrum Quality Product, Inc. (New Brunswick, N.J.), TCIAmerica (Portland, Oreg.), Trans World Chemicals, Inc. (Rockville, Md.),and Wako Chemicals USA, Inc. (Richmond, Va.).

Methods known to one of ordinary skill in the art are identified throughvarious reference books and databases. Suitable reference books andtreatise that detail the synthesis of reactants useful in thepreparation of compounds described herein, or provide references toarticles that describe the preparation include, for example, SYNTHETICORGANIC CHEMISTRY, John Wiley & Sons, Inc., New York; Sandler et al.,ORGANIC FUNCTIONAL GROUP PREPARATIONS, 2nd Ed., Academic Press, NewYork, 1983; House, MODERN SYNTHETIC REACTIONS, 2nd Ed., Benjamin, Inc.Menlo Park, Calif. 1972; Gilchrist, HETEROCYCLIC CHEMISTRY, 2nd Ed.,John Wiley & Sons, New York, 1992; March, ADVANCED ORGANIC CHEMISTRY:REACTIONS, MECHANISMS & STRUCTURE, 4th Ed., Wiley-Interscience, NewYork, 1992. Additional suitable reference books and treatise that detailthe synthesis of reactants useful in the preparation of compoundsdescribed herein, or provide references to articles that describe thepreparation, include, for example, Fuhrhop and Penzlin, ORGANICSYNTHESIS: CONCEPTS, METHODS, STARTING MATERIALS, SECOND, REVISED &ENLARGED EDITION (1994) John Wiley & Sons ISBN: 3-527-29074-5; Hoffman,ORGANIC CHEMISTRY, AN INTERMEDIATE TEXT (1996) Oxford University Press,ISBN 0-19-509618-5; Larock, COMPREHENSIVE ORGANIC TRANSFORMATIONS: AGUIDE TO FUNCTIONAL GROUP PREPARATIONS, 2nd Edition (1999) Wiley-VCH,ISBN: 0-471-19031-4; Otera (editor) MODERN CARBONYL CHEMISTRY (2000)Wiley-VCH, ISBN: 3-527-29871-1; Patai, PATAI'S 1992 GUIDE TO THECHEMISTRY OF FUNCTIONAL GROUPS (1992) Interscience ISBN: 0-471-93022-9;Solomons, ORGANIC CHEMISTRY, 7TH EDITION (2000) John Wiley & Sons, ISBN:0-471-19095-0; Stowell, INTERMEDIATE ORGANIC CHEMISTRY, 2nd Edition(1993) Wiley-Interscience, ISBN: 0-471-57456-2; INDUSTRIAL ORGANICCHEMICALS: STARTING MATERIALS & INTERMEDIATES: AN ULLMANN'S ENCYCLOPEDIA(1999) John Wiley & Sons, ISBN: 3-527-29645-X, in 8 volumes; ORGANICREACTIONS (1942-2000) John Wiley & Sons, in over 55 volumes; andCHEMISTRY OF FUNCTIONAL GROUPS, John Wiley & Sons, in 73 volumes.

Specific and analogous reactants may also be identified through theindices of known chemicals prepared by the Chemical Abstract Service ofthe American Chemical Society, which are available in most public anduniversity libraries, as well as through on-line databases (the AmericanChemical Society, Washington, D.C., may be contacted for more details).Chemicals that are known but not commercially available in catalogs maybe prepared by custom chemical synthesis houses, where many of thestandard chemical supply houses (e.g., those listed above) providecustom synthesis services. A reference for the preparation and selectionof pharmaceutical salts of the substituted heterocyclic derivativecompounds described herein is Stahl & Wermuth, HANDBOOK OFPHARMACEUTICAL SALTS, Verlag Helvetica Chimica Acta, Zurich, 2002.

General methods for the synthesis of substituted heterocyclicderivatives are provided in, but not limited to, the followingreferences: WO 2009/158396; WO 2005/63768; WO 2006/112666; Briet et.al., Tetrahedron (2002), 58(29):5761; WO 2008/77550; WO 2008/77551; WO2008/77556; WO 2007/12421; WO 2007/12422; US 200799911; WO 2008/77550;Havera et al., J. Med. Chem. (1999), 42:3860; WO 2004/29051; and US20090054434. Additional examples of the synthesis of substitutedheterocyclic derivatives are found in the following references: WO2012/171337; WO 2011/044157; WO 2009/097567; WO 2005/030791; EP 203216;Becknell et al., Bioorganic & Medicinal Chem. Letters (2011),21(23):7076; Svechkarev et al., Visnik Kharkivs′kogo Natsional′nogoUniversitetu im. V. N. Karazina (2007), 770:201; Coskun et al.,Synthetic Communications (2005), 35(18):2435; Alvarez et al., Sci.Synth. (2005), 15, 839; Kihara et al., Heterocycles (2000), 53(2):359;Couture et al., J. Chem. Society, Perkin Transactions 1: Org. & Bio-Org.Chem. (1999), (7):789; Kihara et al., Heterocycles (1998), 48(12):2473;Couture et al., Tetrahedron (1996), 52(12), 4433; Couturre et al.,Tetrahedron Letters (1996), 37(21):3697; Natsugari et al., J. Med. Chem.(1995), 38(16):3106; Moehrle et al., Archiv der Pharmazie (Weinheim,Germany) (1988), 321(10):759; Gore et al., J. Chem. Society, PerkinTransactions 1: Org. & Bio-Org. Chem. (1972-1999) (1988), (3):481;Narasimhan et al., J. Chem. Society, Chem. Communc′n (1987), (3):191;Henry et al., J. Org. Chem. (1975), 40(12):1760; Berti, Gazzetta ChimicaItaliana (1960), 90:559; Berti et al., Annali di Chimica (Rome, Italy)(1959), 49:2110; Berti et al., Annali di Chimica (Rome, Italy) (1959),49:1253; WO 2012/000595; Couture et al., Tetrahedron (1996),52(12):4433; WO 2010/069504; WO 2010/069504; WO 2006/030032; WO2005/095384; US20050222159; WO 2013/064984; Mishra et al., Eur. J. Org.Chem. (2013), 2013(4):693; Vachhani et al., Tetrahedron (2013),69(1):359; Xie et al., European J. Med. Chem. (2010), 45(1):210;Mukaiyama et al., Bioorganic & Med. Chem. (2007), 15(2):868;JP2005/089352; Wang et al., Molecules (2004), 9(7):574; WO 2000/023487;US2006/0287341; CN103183675; Hares et al., Egyptian J. Pharm. Sci.(1991), 32(1-2): 303; DE2356005; DE2133898; DE2133998; U.S. Pat. No.3,816,422; DE2011970; and Staehle et al., Justus Liebigs Annalen derChemie (1973), (8):1275.

In some embodiments, the substituted heterocyclic derivative compoundsdisclosed herein are prepared by the general synthetic routes describedbelow in Schemes 1-6. These schemes are intended to exemplary to one ofskill in the art and are not limiting. Additional methods for thesynthesis of the substituted heterocyclic derivative compounds disclosedherein are readily available to one of skill in the art.

A method for preparing compounds of Formula (I) is provided in Scheme 1,above. 6-Bromo-2-methylisoquinolin-1(2H)-one (1-1) is subjected to apalladium-catalyzed cross coupling reaction to provide isoquinolinone1-2. Bromination under acidic conditions provides compound 1-3. Furtherpalladium-catalyzed cross coupling reaction with a boronic acid, orester, provides the isoquinolinone 1-4. Alternatively,palladium-catalyzed cross coupling of compound 1-3 with4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolaneunder the conditions described by Miyaura (Ishiyama et al., J. Org.Chem. 1995, 60, 7508-7510) provides the boron ester 1-5. Furtherpalladium-catalyzed cross coupling reaction of compound 1-5 with asuitable halide provides the isoquinolinone 1-6.

A method for preparing compounds of Formula (I) is provided in Scheme 2,above. 6-Bromo-2-methylisoquinolin-1(2H)-one (2-1) is subjected to apalladium-catalyzed cross coupling reaction with4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolaneto provide boron ester 2-2. Further palladium-catalyzed cross couplingreaction of compound 2-2 with a suitable halide provides compound 2-3.Bromination under acidic conditions provides compound 2-4. Furtherpalladium-catalyzed cross coupling reaction with a boronic acid, orester, provides the isoquinolinone 2-5.

A method for preparing compounds of Formula (II) is provided in Scheme3, above. 5-Bromopyridin-2-ol derivative (3-1) is subjected toalkylation with methyl iodide under basic conditions to provide therelated 5-bromo-1-methylpyridin-2(1H)-one derivative (3-2). Furtherpalladium-catalyzed cross coupling reaction of compound 3-2 with asuitable halide provides compound 3-3.

A method for preparing compounds of Formula (II) is provided in Scheme4, above. 3-Amino-5-bromo-1-methylpyridin-2(1H)-one derivative 4-1 isused as a starting material for several routes. In one route, compound4-1 is directly subjected to a palladium-catalyzed cross couplingreaction to provide pyridone 4-3. The amino group of compound 4-3 issubjected to a reductive amination with an aldehyde and a reducingagent, such as sodium cyanoborohydride, to provide the substituted aminoderivative compound 4-7. A second route involving selective alkylationof the amino group of compound 4-1 begins with protection of the aminogroup as the BOC carbamate. Alkylation of the carbamate under basicconditions followed by removal of the BOC carbamate under acidicconditions provides the secondary amine compound 4-5. Treatment of 4-5with a suitable halide under palladium-catalyzed cross couplingconditions affords compound 4-6.

A method for preparing compounds of Formula (IV) is provided in Scheme5, above. 5-Bromo-1-methylpyrazin-2(1H)-one (5-1) is subjected to animidazole annulation reaction by treatment with tosylmethisocyanide(TosMIC) under basic conditions (Hoogenboom et al., Org. Syntheses,Coll. 6:987 (1988)) to provide5-bromo-7-methylimidazo[1,5-a]pyrazin-8(7H)-one (5-2).Palladium-catalyzed cross coupling reaction of compound 5-2 with asuitable halide provides the compound 5-3.

A method for preparing compounds of Formula (III) is provided in Scheme6, above. 2,6-Naphthyridin-1-ol (6-1) is subjected to alkylation withmethyl iodide under basic conditions to provide2-methyl-2,6-naphthyridin-1(2H)-one (6-2). Chlorination of 6-2 withN-chlorosuccinimide provides chloro compound 6-3. Treatment of 6-3 underpalladium-catalyzed cross coupling conditions with a suitable halideprovides compound 6-4. Selective reduction of the 2,6-naphthyridinonederivative provides the 5,6,7,8-tetrahydro-2,6-naphthyridin-1(2H)-onederivative 6-5.

In each of the above reaction procedures or schemes, the varioussubstituents may be selected from among the various substituentsotherwise taught herein.

Pharmaceutical Compositions

In certain embodiments, the substituted heterocyclic derivative compoundas described herein is administered as a pure chemical. In otherembodiments, the substituted heterocyclic derivative compound describedherein is combined with a pharmaceutically suitable or acceptablecarrier (also referred to herein as a pharmaceutically suitable (oracceptable) excipient, physiologically suitable (or acceptable)excipient, or physiologically suitable (or acceptable) carrier) selectedon the basis of a chosen route of administration and standardpharmaceutical practice as described, for example, in REMINGTON: SCIENCE& PRACTICE OF PHARMACY (Gennaro, 21st Ed. Mack Pub. Co., Easton, Pa.(2005)).

Accordingly, provided herein is a pharmaceutical composition comprisingat least one substituted heterocyclic derivative compound, or astereoisomer, pharmaceutically acceptable salt, hydrate, solvate, orN-oxide thereof, together with one or more pharmaceutically acceptablecarriers. The carrier(s) (or excipient(s)) is acceptable or suitable ifthe carrier is compatible with the other ingredients of the compositionand not deleterious to the recipient (i.e., the subject) of thecomposition.

One embodiment provides a pharmaceutical composition comprising acompound of Formula (I), (Ia), or (Ib), or a pharmaceutically acceptablesalt thereof, and a pharmaceutically acceptable excipient. Oneembodiment provides a pharmaceutical composition comprising a compoundof Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable excipient. One embodimentprovides a pharmaceutical composition comprising a compound of Formula(III), or (IIIa), or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable excipient. One embodiment provides apharmaceutical composition comprising a compound of Formula (IV), or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable excipient. One embodiment provides a pharmaceuticalcomposition comprising a compound of Formula (V), or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable excipient.One embodiment provides a pharmaceutical composition comprising acompound of Formula (VIa), (VIb), (VIc), (VId), or (VIe), or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable excipient. One embodiment provides a pharmaceuticalcomposition comprising a compound of Formula (VII) or (VIIa), or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable excipient. One embodiment provides a pharmaceuticalcomposition comprising a compound of Formula (VIII) or (VIIIa), or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable excipient. One embodiment provides a pharmaceuticalcomposition comprising a compound of Formula (IX), or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable excipient.One embodiment provides a pharmaceutical composition comprising acompound of Formula (XII), or a pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable excipient. One embodimentprovides a pharmaceutical composition comprising a compound of Formula(XIII), or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable excipient. One embodiment provides apharmaceutical composition comprising a compound of Formula (XIV), or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable excipient. One embodiment provides a pharmaceuticalcomposition comprising a compound of Formula (XV), or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable excipient.One embodiment provides a pharmaceutical composition comprising acompound of Formula (XVI), or a pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable excipient. One embodimentprovides a pharmaceutical composition comprising a compound of Formula(XVII), or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable excipient. One embodiment provides apharmaceutical composition comprising a compound of Formula (XVIII), ora pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable excipient. One embodiment provides a pharmaceuticalcomposition comprising a compound of Formula (XIX), or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable excipient. One embodiment provides a pharmaceuticalcomposition comprising a compound of Formula (XX), or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable excipient.One embodiment provides a pharmaceutical composition comprising acompound of Formula (XXI), or a pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable excipient. One embodimentprovides a pharmaceutical composition comprising a compound of Formula(XXII), or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable excipient. One embodiment provides apharmaceutical composition comprising a compound of Formula (XXIII), ora pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable excipient. One embodiment provides a pharmaceuticalcomposition comprising a compound of Formula (XXIV), or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable excipient. One embodiment provides a pharmaceuticalcomposition comprising a compound of Formula (XXV), or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable excipient.

In certain embodiments, the substituted heterocyclic derivative compoundas described herein is substantially pure, in that it contains less thanabout 5%, or less than about 1%, or less than about 0.1%, of otherorganic small molecules, such as contaminating intermediates orby-products that are created, for example, in one or more of the stepsof a synthesis method.

Suitable oral dosage forms include, for example, tablets, pills,sachets, or capsules of hard or soft gelatin, methylcellulose or ofanother suitable material easily dissolved in the digestive tract.Suitable nontoxic solid carriers are used which include, for example,pharmaceutical grades of mannitol, lactose, starch, magnesium stearate,sodium saccharin, talcum, cellulose, glucose, sucrose, magnesiumcarbonate, and the like. See, e.g., REMINGTON: SCIENCE & PRACTICE OFPHARMACY (21st Ed., Gennaro, ed., Mack Pub. Co., Easton, Pa. (2005).

The dose of the composition comprising at least one substitutedheterocyclic derivative compound as described herein may differ,depending upon the patient's (e.g., human) condition, that is, stage ofthe disease, general health status, age, and other factors that a personskilled in the medical art will use to determine dose.

Pharmaceutical compositions may be administered in a manner appropriateto the disease to be treated (or prevented) as determined by personsskilled in the medical arts. An appropriate dose and a suitable durationand frequency of administration will be determined by such factors asthe condition of the patient, the type and severity of the patient'sdisease, the particular form of the active ingredient, and the method ofadministration. In general, an appropriate dose and treatment regimenprovides the composition(s) in an amount sufficient to providetherapeutic and/or prophylactic benefit (e.g., an improved clinicaloutcome, such as more frequent complete or partial remissions, or longerdisease-free and/or overall survival, or a lessening of symptomseverity. Optimal doses may generally be determined using experimentalmodels and/or clinical trials. The optimal dose may depend upon the bodymass, weight, or blood volume of the patient.

Oral doses typically range from about 1.0 mg to about 1000 mg, one tofour times, or more, per day.

Bromodomain Inhibition

Chromatin is the complex of DNA and protein that makes up chromosomes.Histones are the major protein component of chromatin, acting as spoolsaround which DNA winds. Changes in chromatin structure are affected bycovalent modifications of histone proteins and by non-histone bindingproteins. Several classes of enzymes are known which modify histones atvarious sites. Epigenetics is the study of heritable changes in geneexpression caused by mechanisms other than the underlying DNA sequence.Molecular mechanisms that play a role in epigenetic regulation includeDNA methylation and chromatin/histone modifications.

The genomes of eukaryotic organisms are highly organized within thenucleus of the cell. Tremendous compaction is required to package the 3billion nucleotides of the human genome into the nucleus of a cell.

Histones are the chief protein components of chromatin. There are atotal of six classes of histones (H1, H2A, H2B, H3, H4, and H5)organized into two classes: core histones (H2A, H2B, H3, and H4) andlinker histones (H1 and H5). The basic unit of chromatin is thenucleosome, which consists of about 147 base pairs of DNA wrapped aroundthe core histone octamer, consisting of two copies each of the corehistones H2A, H2B, H3, and H4.

Basic nucleosome units are then further organized and condensed by theaggregation and folding of nucleosomes to form a highly condensedchromatin structure. A range of different states of condensation arepossible, and the tightness of chromatin structure varies during thecell cycle, being most compact during the process of cell division.

Chromatin structure plays a critical role in regulating genetranscription, which cannot occur efficiently from highly condensedchromatin. The chromatin structure is controlled by a series of posttranslational modifications to histone proteins, notably histones H3 andH4, and most commonly within the histone tails which extend beyond thecore nucleosome structure. These modifications include acetylation,methylation, phosphorylation, ribosylation sumoylation, ubiquitination,citrullination, deimination, and biotinylation. The core of histones H2Aand H3 can also be modified. Histone modifications are integral todiverse biological processes such as gene regulation, DNA repair, andchromosome condensation.

Histone Acetylation and Bromodomains

Histone acetylation is generally associated with the activation of genetranscription, as the modification is known to loosen the interaction ofthe DNA and the histone octamer by changing the electrostatics. Inaddition to this physical change, specific proteins are known to bind toacetylated lysine residues within histones in order to read theepigenetic code. Bromodomains are small (˜110 amino acid) distinctdomains within proteins that are known to bind to acetylated lysineresidues commonly, but not exclusively, in the context of histones.Around 50 proteins are known to contain bromodomains, and they have arange of functions within the cell.

The BET family of bromodomain containing proteins comprises 4 proteins(BRD2, BRD3, BRD4 and BRD-t) which contain tandem bromodomains capableof binding to two acetylated lysine resides in close proximity,increasing the specificity of the interaction.

Bromodomain-containing proteins that recognize acetylated lysines onhistones (such as BET proteins and non-BET proteins) have beenimplicated in proliferative disease. BRD4 knockout mice die shortlyafter implantation and are compromised in their ability to maintain aninner cell mass, and heterozygotes display pre- and postnatal growthdefects associated with reduced proliferation rates. BRD4 regulatesgenes expressed during M/Gl, including growth-associated genes, andremains bound to chromatin throughout the cell cycle (Dey et al. (2009)Mol. Biol. Cell 20:4899). BRD4 also physically associates with Mediatorand P-TEFb (CDK9/cyclin Tl) to facilitate transcriptional elongation(Yang et al. (2005) Oncogene 24:1653; Yang, et al. (2005) Mol. Cell19:535). CDK9 is a validated target in chronic lymphocytic leukemia(CLL), and is linked to c-Myc-dependent transcription (Phelps et al.Blood 113:2637; Rahl et al. (2010) Cell 141:432).

BRD4 is translocated to the NUT protein in patients with lethal midlinecarcinoma, an aggressive form of human squamous carcinoma. French, etal. (2001) Am. J. Pathol. 159:1987; French et al. (2003) Cancer Res.63:304. In vitro analysis with RNAi supports a causal role for BRD4 inthis recurrent t(15; 19) chromosomal translocation. Also, inhibition ofthe BRD4 bromodomains has been found to result in growtharrest/differentiation of BRD4-NUT cell lines in vitro and in vivo(Filippakopoulos et al., Selective Inhibition of BET Bromodomains,Nature (published online Sep. 24, 2010)).

Bromodomain-containing proteins (such as BET proteins) have also beenimplicated in inflammatory diseases. BET proteins (e.g., BRD2, BRD3,BRD4, and BRDT) regulate assembly of histone acetylation-dependentchromatin complexes that control inflammatory gene expression.Hargreaves et al. (2009) Cell 138:129; LeRoy et al. (2008) Mol. Cell30:51; Jang, et al. (2005) Mol. Cell 19:523; Yang, et al. (2005) Mol.Cell 19:535. Key inflammatory genes (secondary response genes) aredown-regulated upon bromodomain inhibition of the BET subfamily, andnon-responsive genes (primary response genes) are poised fortranscription. BET bromodomain inhibition protects against LPS-inducedendotoxic shock and bacteria-induced sepsis in vivo (Nicodeme et al.,Suppression of Inflammation by a Synthetic Histone Mimic, Nature(published online Nov. 10, 2010)).

Bromodomain-containing proteins (such as BET proteins) have also beenfound to play a role in viral infection. For example, BRD4 is implicatedin the primary phase of human papilloma virus (HPV) infection, in whichthe viral genome is maintained in an extra-chromosomal episome in basalepithelia. In some strains of HPV, BRD4 binding to the HPV E2 proteinfunctions to tether the viral genome to chromosomes. E2 is critical forboth the repression of E6/E7 and the activation of HPV viral genes.Disruption of BRD4 or the BRD4-E2 interaction blocks E2-dependent geneactivation. BRD4 also functions to tether other classes of viral genomesto host chromatin (e.g., Herpes virus, Epstein-Barr virus).

Bromodomain-containing proteins has also been found to bind toacetylated lysine residues on proteins other than histones. For example,the bromodomain of CREB binding protein transcriptional coactivator(CBP) allows for recognition of p53 with acetylated Lys382. Theinteraction between the bromodomain and acetyl-p53 follows DNA damageand promotes p53-induced transcriptional activation of the CDK inhibitorp21 and cell cycle arrest. Another novel bromodomain-containing proteinis BAZ2B, whose biological function, is believed to function similarlyto ACF1, the Drosophila BAZ2B ortholog. ACF complexes play roles inestablishing regular nucleosome spacing during chromatin assembly andinfluencing different remodeling outcomes at target loci.

One embodiment provides a method of regulating gene transcription in acell comprising exposing a bromodomain containing protein to a compoundof Formula (I), (Ia), or (Ib). One embodiment provides a method ofregulating gene transcription in a cell comprising exposing abromodomain containing protein to a compound of Formula (II), (IIa), or(IIb). One embodiment provides a method of regulating gene transcriptionin a cell comprising exposing a bromodomain containing protein to acompound of Formula (III), or (IIIa). One embodiment provides a methodof regulating gene transcription in a cell comprising exposing abromodomain containing protein to a compound of Formula (IV). Oneembodiment provides a method of regulating gene transcription in a cellcomprising exposing a bromodomain containing protein to a compound ofFormula (V). One embodiment provides a method of regulating genetranscription in a cell comprising exposing a bromodomain containingprotein to a compound of Formula (VIa), (VIb), (VIc), (VId), or (VIe).One embodiment provides a method of regulating gene transcription in acell comprising exposing a bromodomain containing protein to a compoundof Formula (VII) or (VIIa). One embodiment provides a method ofregulating gene transcription in a cell comprising exposing abromodomain containing protein to a compound of Formula (VIII), or(VIIIa). One embodiment provides a method of regulating genetranscription in a cell comprising exposing a bromodomain containingprotein to a compound of Formula (IX). One embodiment provides a methodof regulating gene transcription in a cell comprising exposing abromodomain containing protein to a compound of Formula (XII). Oneembodiment provides a method of regulating gene transcription in a cellcomprising exposing a bromodomain containing protein to a compound ofFormula (XIII). One embodiment provides a method of regulating genetranscription in a cell comprising exposing a bromodomain containingprotein to a compound of Formula (XIV). One embodiment provides a methodof regulating gene transcription in a cell comprising exposing abromodomain containing protein to a compound of Formula (XV). Oneembodiment provides a method of regulating gene transcription in a cellcomprising exposing a bromodomain containing protein to a compound ofFormula (XVI). One embodiment provides a method of regulating genetranscription in a cell comprising exposing a bromodomain containingprotein to a compound of Formula (XVII). One embodiment provides amethod of regulating gene transcription in a cell comprising exposing abromodomain containing protein to a compound of Formula (XVIII). Oneembodiment provides a method of regulating gene transcription in a cellcomprising exposing a bromodomain containing protein to a compound ofFormula (XIX). One embodiment provides a method of regulating genetranscription in a cell comprising exposing a bromodomain containingprotein to a compound of Formula (XX). One embodiment provides a methodof regulating gene transcription in a cell comprising exposing abromodomain containing protein to a compound of Formula (XXI). Oneembodiment provides a method of regulating gene transcription in a cellcomprising exposing a bromodomain containing protein to a compound ofFormula (XXII). One embodiment provides a method of regulating genetranscription in a cell comprising exposing a bromodomain containingprotein to a compound of Formula (XXIII). One embodiment provides amethod of regulating gene transcription in a cell comprising exposing abromodomain containing protein to a compound of Formula (XXIV). Oneembodiment provides a method of regulating gene transcription in a cellcomprising exposing a bromodomain containing protein to a compound ofFormula (XXV).

One embodiment provides a method of inhibiting bromodomain-mediatedrecognition of an acetyl lysine region of a protein comprising exposingthe bromodomain to a compound of Formula (I), (Ia), or (Ib). Oneembodiment provides a method of inhibiting bromodomain-mediatedrecognition of an acetyl lysine region of a protein comprising exposingthe bromodomain to a compound of Formula (II), (IIa), or (IIb). Oneembodiment provides a method of inhibiting bromodomain-mediatedrecognition of an acetyl lysine region of a protein comprising exposingthe bromodomain to a compound of Formula (III) or (IIIa). One embodimentprovides a method of inhibiting bromodomain-mediated recognition of anacetyl lysine region of a protein comprising exposing the bromodomain toa compound of Formula (IV). One embodiment provides a method ofinhibiting bromodomain-mediated recognition of an acetyl lysine regionof a protein comprising exposing the bromodomain to a compound ofFormula (V). One embodiment provides a method of inhibitingbromodomain-mediated recognition of an acetyl lysine region of a proteincomprising exposing the bromodomain to a compound of Formula (VIa),(VIb), (VIc), (VId), or (VIe). One embodiment provides a method ofinhibiting bromodomain-mediated recognition of an acetyl lysine regionof a protein comprising exposing the bromodomain to a compound ofFormula (VII) or (VIla). One embodiment provides a method of inhibitingbromodomain-mediated recognition of an acetyl lysine region of a proteincomprising exposing the bromodomain to a compound of Formula (VIII), or(VIIIa). One embodiment provides a method of inhibitingbromodomain-mediated recognition of an acetyl lysine region of a proteincomprising exposing the bromodomain to a compound of Formula (IX). Oneembodiment provides a method of inhibiting bromodomain-mediatedrecognition of an acetyl lysine region of a protein comprising exposingthe bromodomain to a compound of Formula (XII). One embodiment providesa method of inhibiting bromodomain-mediated recognition of an acetyllysine region of a protein comprising exposing the bromodomain to acompound of Formula (XIII) One embodiment provides a method ofinhibiting bromodomain-mediated recognition of an acetyl lysine regionof a protein comprising exposing the bromodomain to a compound ofFormula (XIV). One embodiment provides a method of inhibitingbromodomain-mediated recognition of an acetyl lysine region of a proteincomprising exposing the bromodomain to a compound of Formula (XV). Oneembodiment provides a method of inhibiting bromodomain-mediatedrecognition of an acetyl lysine region of a protein comprising exposingthe bromodomain to a compound of Formula (XVI). One embodiment providesa method of inhibiting bromodomain-mediated recognition of an acetyllysine region of a protein comprising exposing the bromodomain to acompound of Formula (XVII). One embodiment provides a method ofinhibiting bromodomain-mediated recognition of an acetyl lysine regionof a protein comprising exposing the bromodomain to a compound ofFormula (XVIII). One embodiment provides a method of inhibitingbromo-domain-mediated recognition of an acetyl lysine region of aprotein comprising exposing the bromodomain to a compound of Formula(XIX). One embodiment provides a method of inhibitingbromodomain-mediated recognition of an acetyl lysine region of a proteincomprising exposing the bromodomain to a compound of Formula (XX). Oneembodiment provides a method of inhibiting bromodomain-mediatedrecognition of an acetyl lysine region of a protein comprising exposingthe bromodomain to a compound of Formula (XXI). One embodiment providesa method of inhibiting bromodomain-mediated recognition of an acetyllysine region of a protein comprising exposing the bromodomain to acompound of Formula (XXII). One embodiment provides a method ofinhibiting bromodomain-mediated recognition of an acetyl lysine regionof a protein comprising exposing the bromodomain to a compound ofFormula (XXIII) One embodiment provides a method of inhibitingbromodomain-mediated recognition of an acetyl lysine region of a proteincomprising exposing the bromodomain to a compound of Formula (XXIV). Oneembodiment provides a method of inhibiting bromodomain-mediatedrecognition of an acetyl lysine region of a protein comprising exposingthe bromodomain to a compound of Formula (XXV).

One embodiment provides a method of regulating gene transcription in acell comprising exposing a bromodomain-containing protein to a compoundof Formula (X), or a pharmaceutically acceptable salt thereof,

-   -   wherein,    -   R² is selected from CH₃, CH₂CH₃, CH₂CF₃, CH₂F, CHF₂, CF₃, CH₂D,        CHD₂, or CD₃;    -   X5 is C—R⁵ or N;    -   X6 is C—R⁶ or N;    -   X7 is C—R⁷ or N;    -   X8 is C—R⁸ or N; wherein no more than two of X5, X6, X7, or X8        may be N;    -   R⁵ is hydrogen, halogen, —OH, —CN, —OR⁶¹, —NHR⁶¹, —N(R⁶¹)₂,        alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,        heterocyclylalkyl, heteroaryl, or heteroarylalkyl, wherein each        R⁶¹ is independently selected from alkyl, cycloalkyl,        cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,        heteroaryl, or heteroarylalkyl;    -   R⁶ is hydrogen, halogen, —OH, —CN, —OR⁶¹, —NHR⁶¹, —N(R⁶¹)₂,        alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,        heterocyclylalkyl, heteroaryl, or heteroarylalkyl, wherein each        R⁶¹ is independently selected from alkyl, cycloalkyl,        cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,        heteroaryl, or heteroarylalkyl;    -   R⁷ is hydrogen, halogen, —OH, —CN, —OR⁶¹, —NHR⁶¹, —N(R⁶¹)₂,        alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,        heterocyclylalkyl, heteroaryl, or heteroarylalkyl, wherein each        R⁶¹ is independently selected from alkyl, cycloalkyl,        cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,        heteroaryl, or heteroarylalkyl;    -   R⁸ is hydrogen, halogen, or alkyl; and    -   R^(A) is an aryl group or a heteroaryl group.

Another embodiment provides the method of regulating gene transcriptionin a cell, wherein the compound of Formula (X) has the structure whereinR^(A) is a substituted phenyl group.

Another embodiment provides a method of inhibiting ofbromodomain-mediated recognition of an acetyl lysine region of a proteincomprising exposing the bromodomain to a compound of Formula (X).Another embodiment provides the method of inhibiting ofbromodomain-mediated recognition of an acetyl lysine region of aprotein, wherein the compound of Formula (X) has the structure whereinR^(A) is a substituted phenyl group.

One embodiment provides a method of regulating gene transcription in acell comprising exposing a bromodomain-containing protein to a compoundof Formula (XI), or a pharmaceutically acceptable salt thereof,

-   -   wherein,    -   R² is CH₃, CH₂CH₃, CH₂CF₃, CH₂F, CHF₂, CF₃, CH₂D, CHD₂, or CD₃;    -   X3 is C—H or N;    -   X5 is C—R⁵ or N; provided that if X3 is N, then X5 is C—R⁵, and        if X5 is N, then X3 is CH;    -   R⁵ is hydrogen, halogen, —OH, —CN, —OR⁶¹, —NHR⁶¹, —N(R⁶¹)₂,        alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,        heterocyclylalkyl, heteroaryl, or heteroarylalkyl, wherein each        R⁶¹ is independently selected from alkyl, cycloalkyl,        cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,        heteroaryl, or heteroarylalkyl;    -   R⁶ is hydrogen, halogen, —OH, —CN, alkyl, cycloalkyl,        cycloalkylalkyl, amino, alkylamino, dialkylamino,        cycloalkylalkylamino, alkoxy, or cycloalkylalkoxy; and R^(A) is        an aryl group or a heteroaryl group.

Another embodiment provides the method of regulating gene transcriptionin a cell, wherein the compound of Formula (XI) has the structurewherein RA is a substituted phenyl group.

Another embodiment provides a method of inhibiting ofbromodomain-mediated recognition of an acetyl lysine region of a proteincomprising exposing the bromodomain to a compound of Formula (XI).Another embodiment provides the method of inhibiting ofbromodomain-mediated recognition of an acetyl lysine region of aprotein, wherein the compound of Formula (XI) has the structure whereinRA is a substituted phenyl group.

Methods of Treatment

Compounds and compositions described herein are generally useful for theinhibition of activity of one or more proteins involved in epigeneticregulation. Thus, one embodiment provides a method of modulatingepigenetic regulation mediated by one or more proteins containingacetyl-lysine recognition motifs, also known as bromodomains (e.g., BETproteins, such as BRD2, BRD3, BRD4, and/or BRDT, and non-BET proteins,such as CBP, ATAD2A, GCN5L, BAZ2B, FALZ, TAF1, and/or BRPF1), byadministering a substituted heterocyclic derivative compound asdescribed herein.

In some embodiments, the substituted heterocyclic derivative compoundsas described herein are capable of inhibiting the activity of abromodomain-containing protein, such as a BET protein (BRD2, BRD3, BRD4and/or BRDT), non-BET proteins (such as CBP, ATAD2A, GCN5L, BAZ2B, FALZ,TAF1, and/or BRPF1) or a mutant thereof, in a biological sample inmanner useful for a variety of purposes that are known to one of skillin the art. Examples of such purposes include, but are not limited to,blood transfusion, organ-transplantation, biological specimen storage,and biological assays.

In some embodiments is provided a method of inhibiting the activity of abromodomain-containing protein, such as a BET protein (BRD2, BRD3, BRD4and/or BRDT), non-BET proteins (such as CBP, ATAD2A, GCN5L, BAZ2B, FALZ,TAF1, and/or BRPF1) or a mutant thereof, in a patient comprising thestep of administering to said patient a substituted heterocyclicderivative compound as described herein, or a composition comprisingsaid compound.

In some embodiments is provided a method of inhibiting the activity of abromodomain-containing protein, such as a BET protein (BRD2, BRD3, BRD4and/or BRDT), non-BET proteins (such as CBP, ATAD2A, GCN5L, BAZ2B, FALZ,TAF1, and/or BRPF1) or a mutant thereof, in a biological samplecomprising the step of contacting said biological sample with asubstituted heterocyclic derivative compound as described herein. Insome embodiments, the bromodomain-containing protein is a BET protein.In some embodiments, the BET protein is BRD4.

In some embodiments is provided a method of inhibiting the activity of abromodomain-containing protein, such as a BET protein (BRD2, BRD3, BRD4and/or BRDT), non-BET proteins (such as CBP, ATAD2A, GCN5L, BAZ2B, FALZ,TAF1, and/or BRPF1) or a mutant thereof, in a patient in need thereof,comprising the step of administering to said patient a substitutedheterocyclic derivative compound as described herein. In someembodiments, the bromodomain-containing protein is a BET protein. Insome embodiments, the BET protein is BRD4.

Diseases and conditions treatable according to the methods of thisinvention include cancer, neoplastic disease and other proliferativedisorders. Thus, one aspect is a method of treating a subject havingcancer, a neoplastic disease and other proliferative disorder, themethod comprising administration of a substituted heterocyclicderivative compound as described herein to the subject. In oneembodiment, a human patient is treated with a substituted heterocyclicderivative compound as described herein and a pharmaceuticallyacceptable excipient, wherein said compound is present in an amount tomeasurably inhibit bromodomain-containing protein activity (such asBRD2, BRD3, BRD4, and/or BRDT) in the patient.

The invention further provides a method of treating a subject, such as ahuman, suffering from cancer, a neoplastic disease and otherproliferative disorder. The method comprises administering to a subjectin need of such treatment a therapeutically effective amount of one ormore substituted heterocyclic derivative compound as described herein,which function by inhibiting a bromodomain and, in general, bymodulating gene expression, to induce various cellular effects, inparticular induction or repression of gene expression, arresting cellproliferation, inducing cell differentiation and/or inducing apoptosis.

The invention further provides a therapeutic method of modulatingprotein methylation, gene expression, cell proliferation, celldifferentiation and/or apoptosis in vivo in conditions, illnesses,disorders or diseases disclosed herein, in particular cancer,inflammatory disease, and/or viral disease comprising administering to asubject in need of such therapy a pharmacologically active andtherapeutically effective amount of one or more substituted heterocyclicderivative compound as described herein.

The invention further provides a method of regulating endogenous orheterologous promoter activity by contacting a cell with a substitutedheterocyclic derivative compound as described herein.

The invention further relates to a method for treating or amelioratingcancer, neoplastic disease, or another proliferative disorder byadministration of an effective amount of a substituted heterocyclicderivative compound as described herein, to a mammal, in particular ahuman, in need of such treatment. In some aspects of the invention, thedisease to be treated by the methods of the present invention is cancer.

In certain embodiments, the cancer is NUT midline carcinoma, prostatecancer, breast cancer, bladder cancer, lung cancer, or melanoma. Inanother embodiment the cancer is Burkitts lymphoma.

One embodiment provides a method of treating cancer in a patient in needthereof, comprising administering to the patient a compound of Formula(I), (Ia), or (Ib), or a pharmaceutically acceptable salt thereof. Oneembodiment provides a method of treating cancer in a patient in needthereof, comprising administering to the patient a compound of Formula(II), (IIa), or (IIb), or a pharmaceutically acceptable salt thereof.One embodiment provides a method of treating cancer in a patient in needthereof, comprising administering to the patient a compound of Formula(III), or (IIIa), or a pharmaceutically acceptable salt thereof. Oneembodiment provides a method of treating cancer in a patient in needthereof, comprising administering to the patient a compound of Formula(IV), or a pharmaceutically acceptable salt thereof. One embodimentprovides a method of treating cancer in a patient in need thereof,comprising administering to the patient a compound of Formula (V), or apharmaceutically acceptable salt thereof. One embodiment provides amethod of treating cancer in a patient in need thereof, comprisingadministering to the patient a compound of Formula (VIa), (VIb), (VIc),(VId), or (VIe), or a pharmaceutically acceptable salt thereof. Oneembodiment provides a method of treating cancer in a patient in needthereof, comprising administering to the patient a compound of Formula(VII) or (VIIa), or a pharmaceutically acceptable salt thereof. Oneembodiment provides a method of treating cancer in a patient in needthereof, comprising administering to the patient a compound of Formula(VIII) or (VIIIa), or a pharmaceutically acceptable salt thereof. Oneembodiment provides a method of treating cancer in a patient in needthereof, comprising administering to the patient a compound of Formula(IX), or a pharmaceutically acceptable salt thereof. One embodimentprovides a method of treating cancer in a patient in need thereof,comprising administering to the patient a compound of Formula (XII), ora pharmaceutically acceptable salt thereof. One embodiment provides amethod of treating cancer in a patient in need thereof, comprisingadministering to the patient a compound of Formula (XIII), or apharmaceutically acceptable salt thereof. One embodiment provides amethod of treating cancer in a patient in need thereof, comprisingadministering to the patient a compound of Formula (XIV), or apharmaceutically acceptable salt thereof. One embodiment provides amethod of treating cancer in a patient in need thereof, comprisingadministering to the patient a compound of Formula (XV), or apharmaceutically acceptable salt thereof. One embodiment provides amethod of treating cancer in a patient in need thereof, comprisingadministering to the patient a compound of Formula (XVI), or apharmaceutically acceptable salt thereof. One embodiment provides amethod of treating cancer in a patient in need thereof, comprisingadministering to the patient a compound of Formula (XVII), or apharmaceutically acceptable salt thereof. One embodiment provides amethod of treating cancer in a patient in need thereof, comprisingadministering to the patient a compound of Formula (XVIII), or apharmaceutically acceptable salt thereof. One embodiment provides amethod of treating cancer in a patient in need thereof, comprisingadministering to the patient a compound of Formula (XIX), or apharmaceutically acceptable salt thereof. One embodiment provides amethod of treating cancer in a patient in need thereof, comprisingadministering to the patient a compound of Formula (XX), or apharmaceutically acceptable salt thereof. One embodiment provides amethod of treating cancer in a patient in need thereof, comprisingadministering to the patient a compound of Formula (XXI), or apharmaceutically acceptable salt thereof. One embodiment provides amethod of treating cancer in a patient in need thereof, comprisingadministering to the patient a compound of Formula (XXII), or apharmaceutically acceptable salt thereof. One embodiment provides amethod of treating cancer in a patient in need thereof, comprisingadministering to the patient a compound of Formula (XXIII), or apharmaceutically acceptable salt thereof. One embodiment provides amethod of treating cancer in a patient in need thereof, comprisingadministering to the patient a compound of Formula (XXIV), or apharmaceutically acceptable salt thereof. One embodiment provides amethod of treating cancer in a patient in need thereof, comprisingadministering to the patient a compound of Formula (XXV), or apharmaceutically acceptable salt thereof.

Other embodiments and uses will be apparent to one skilled in the art inlight of the present disclosures. The following examples are providedmerely as illustrative of various embodiments and shall not be construedto limit the invention in any way.

Examples I. Chemical Synthesis

Unless otherwise noted, reagents and solvents were used as received fromcommercial suppliers. Anhydrous solvents and oven-dried glassware wereused for synthetic transformations sensitive to moisture and/or oxygen.Yields were not optimized. Reaction times are approximate and were notoptimized. Column chromatography (CC) and thin layer chromatography(TLC) were performed on silica gel unless otherwise noted. Spectra aregiven in ppm (δ) and coupling constants (J) are reported in Hertz. For¹H NMR spectra, the solvent peak was used as the reference peak.

Chemistry Example 1 is 2-methyl-4-phenylisoquinolin-1-one which waspurchased from a commercial vendor.

Example 2: 4-(3-methoxyphenyl)-2-methylisoquinolin-1-one

A mixture of 4-bromo-2-methylisoquinolin-1(2H)-one (100 mg, 0.42 mmol),and (3-methoxyphenyl)boronic acid (70 mg, 0.46 mmol), PPh₃ (66 mg, 0.25mmol), Na₂CO₃ (133 mg, 1.26 mmol), and Pd(dppf)Cl₂ (62 mg, 0.084 mmol)in dioxane (2.5 mL) and H₂O (0.5 mL) was heated overnight at 90° C.Extractive work-up with EtOAc followed by preparative TLC (PE:EA=1:1)gave the title compound (18 mg, 0.07 mmol) as a white solid in 17%yield. ¹H NMR (DMSO, 400 MHz): δ 8.30 (d, 1H, J=7.68), 7.68 (t, 1H,J=7.56), 7.50-7.55 (m, 3H), 7.40 (t, 1H, J=7.44), 6.97-7.00 (m, 3H),3.78 (s, 3H), 3.54 (s, 3H). MS (m/z, relative intensity): 266 (Mt 1).

Examples 3-14: in Table 3 were prepared from4-bromo-2-methylisoquinolin-1(2H)-one and the appropriate boronicacid/ester in a manner similar to Example 2.

TABLE 3

Ex. ¹H NMR MS No. R¹ Name (ppm (d), 400 MHz) (M + H)  3

4-(2-fluorophenyl)-2- methylisoquinolin-1-one (DMSO-d₆) 3.57 (s, 3 H)7.20 (d, J = 7.42 Hz, 1H) 7.31-7.41 (m, 2H) 7.42-7.61 (m, 4H) 7.64-7.73(m, 1H) 8.32 (d, J = 7.81 Hz, 1H) 254  4

4-(2-methoxyphenyl)-2- methylisoquinolin-1-one (DMSO-d₆) 3.54 (s, 3 H)3.67 (s, 3 H) 7.00-7.11 (m, 2H) 7.15 (d, J = 8.20 Hz, 1H) 7.25 (d, J =6.83 Hz, 1H) 7.40 (s, 1H) 7.48 (dt, J = 15.91, 7.86 Hz, 2H) 7.61 (d, J =7.42 Hz, 1H) 8.28 (d, J = 8.20 Hz, 1H) 266  5

4-(3-aminophenyl)-2- methylisoquinolin-1-one (DMSO-d₆) 3.55 (s, 3 H)5.19 (br. s., 2H) 6.55 (d, J = 7.33 Hz, 1H) 6.60-6.64 (m, 2 H) 7.12 (t,J = 7.83 Hz, 1H) 7.43 (s, 1H) 7.51-7.62 (m, 2 H) 7.66-7.72 (m, 1H) 8.31(d, J = 7.83 Hz, 1H) 251  6

N-cyclopropyl-3-(2-methyl-1- oxoisoquinolin-4-yl) benzenesulfonamide(DMSO-d₆) 0.36-0.41 (m, 2H) 0.47-0.52 (m, 2 H) 2.16 (br. s., 1H) 3.57(s, 3 H) 7.44 (d, J = 8.20 Hz, 1 H) 7.54-7.61 (m, 2 H) 7.68- 7.77 (m,3H) 7.83-7.88 (m, 2H) 7.96 (br. s., 1H) 8.34 (d, J = 7.81 355 Hz, 1H)  7

2-methyl-4-(3-pyrrolidin-1-yl- sulfonylphenyl)isoquinolin-1- one(DMSO-d₆) 1.67 (t, J = 6.64 Hz, 4H) 3.18 (t, J = 6.44 Hz, 4H) 3.57 (s,3H) 7.42 (d, J = 8.20 Hz, 1H) 7.56 (t, J = 7.61 Hz, 1H) 7.61 (s, 1H)7.68-7.80 (m, 4H) 7.85 (d, J = 6.83 Hz, 1H) 8.33 (d, J = 8.20 369 Hz,1H)  8

N-[[3-(2-methyl-1- oxoisoquinolin-4-yl) phenyl]methyl]methanesulfonamide (DMSO-d₆) 2.87 (s, 3H) 3.56 (s, 3H) 4.22 (d, J = 6.05Hz, 2H) 7.31- 7.44 (m, 3H) 7.45-7.62 (m, 5H) 7.64-7.72 (m, 1H) 8.32 (d,J = 7.61 Hz, 1H) 343  9

N-[3-(2-methyl-1- oxoisoquinolin-4-yl) phenyl]methanesulfonamide(DMSO-d₆) 3.03 (s, 3 H) 3.55 (s, 3H) 7.16 (d, J = 7.61 Hz, 1 H) 7.23-7.28 (m, 2H) 7.45 (t, J = 8.30 Hz, 1H) 7.48-7.57 (m, 3 H) 7.67-7.72 (m,1H) 8.31 (d, J = 7.03 Hz, 1H) 9.88 (br. s., 1 H) 329 10

N-ethyl-3-(2-methyl-1- oxoisoquinolin-4-yl) benzenesulfonamide (DMSO-d₆)0.92-1.02 (m, 3H) 2.76-2.86 (m, 2 H) 3.56 (s, 3H) 7.43 (d, J = 8.20 Hz,1H) 7.53-7.60 (m, 2H) 7.64 (t, J = 5.66 Hz, 1H) 7.68-7.75 (m, 3 H)7.80-7.88 (m, 2H) 8.29-8.36 (m, 1H) 343 11

4-(3-ethylsulfonylphenyl)-2- methylisoquinolin-1-one (CHLOROFORM-d) 1.33(t, J = 7.42 Hz, 3H) 3.18 (q, J = 7.42 Hz, 2H) 3.65-3.69 (m, 3H) 7.10(s, 1 H) 7.43 (d, J = 8.01 Hz, 1H) 7.51-7.57 (m, 1 H) 7.60-7.76 (m, 3H)7.93-7.98 (m, 2 H) 8.53 (dd, 328 J = 8.01, 0.98 Hz, 1H) 12

4-[3- (dimethylsulfamoylamino)phe- nyl]-2-methyl-1- oxoisoquinoline(DMSO-d₆) 2.71 (s, 6 H) 3.55 (s, 3H) 7.10 (d, J = 7.03 Hz, 1H) 7.22-7.25 (m, 2H) 7.41 (t, J = 7.71 Hz, 1H) 7.48 (s, 1H) 7.50-7.56 (m, 2H)7.67-7.72 (m, 1H) 8.31 (d, J = 7.81 Hz, 1H) 10.02 (br. s., 1H) 358 13

N-[3-(2-methyl-1- oxoisoquinolin-4-yl) phenyl]ethanesulfonamide(DMSO-d₆) 1.20 (t, J = 7.13 Hz, 3H) 3.13 (q, J = 7.29 Hz, 2H) 3.55 (s,3H) 7.14 (d, J = 7.03 Hz, 1H) 7.25 (br. s., 2 H) 7.38-7.59 (m, 4H) 7.69(t, J = 7.61 Hz, 1H) 8.31 (d, J = 8.01 Hz, 1H) 9.92 (s, 1H) 343 14

2-methyl-4-(3-morpholin- 4-yl-sulfonylphenyl) isoquinolin-1-one(DMSO-d₆) 3.02-3.09 (m, 4H) 3.68 (s, 3 H) 3.73-3.80 (m, 4H) 7.09 (s, 1H) 7.43 (d, J = 7.81 Hz, 1H) 7.53-7.58 (m, 1H) 7.61-7.73 (m, 3H)7.78-7.84 (m, 2H) 8.55 (d, J = 7.03 Hz, 1H) 385

Example 15:N-benzyl-2-methoxy-5-(2-methyl-1-oxoisoquinolin-4-yl)benzenesulfonamide

For about 3 min, N₂ was bubbled through the mixture of4-bromo-2-methylisoquinolin-1(2H)-one (56 mg, 0.24 mmol),[3-(benzylsulfamoyl)-4-methoxyphenyl]boronic acid (83 mg, 0.26 mmol), aq2M Na₂CO₃ (0.375 mL) and Pd(dppf)Cl₂ (9 mg, 0.001 mmol) in dioxane (1.5mL) which was then microwaved at 120° C. for 1 hr and then filteredthrough a plug of anhydrous Na₂SO₄ using EtOAc to transfer and rinse.Silica gel chromatography, eluting with 0-60% EA in hexane over 6 minand continuing 60% isocratic EA gave the title compound (60 mg, 0.14mmol) as a white solid in 58% yield. ¹H NMR (400 MHz, DMSO-d₆): δ 3.57(s, 3H), 3.89 (s, 3H), 4.11 (d, J=6.32 Hz, 2H), 7.16-7.23 (m, 6H), 7.34(d, J=8.08 Hz, 1H), 7.47 (s, 1H), 7.53-7.59 (m, 2H), 7.65 (d, J=2.27 Hz,1H), 7.72-7.77 (m, 1H), 7.94 (t, J=6.32 Hz, 1H), 8.34 (d, J=7.33 Hz,1H). LCMS (M+H)⁺: 435.

Examples 16-17 in Table 4 were prepared from4-bromo-2-methylisoquinolin-1(2H)-one and the appropriate boronicacid/ester in a manner similar to Example 15.

TABLE 4

Ex. ¹H NMR MS No. R¹ Name (ppm (d), 400 MHz) (M + H) 16

2-methoxy-5-(2-methyl-1- oxoisoquinolin-4-yl) benzenesulfonamide(DMSO-d₆) 3.57 (s, 3 H) 3.97 (s, 3H) 7.18 (s, 2H) 7.35 (d, J = 8.59 Hz,1H) 7.44 (d, J = 8.08 Hz, 1H) 7.50 (s, 1H) 7.57 (t, J = 7.45 Hz, 1H)7.65 (dd, J = 8.46, 2.15 Hz, 1H) 7.71 (t, J = 7.58 Hz, 1 H) 7.76 (d, J =2.27 Hz, 345 1H) 8.34 (d, J = 8.34 Hz, 1H) 17

N-[2-methyl-5-(2-methyl-1- oxoisoquinolin-4-yl)phenyl]methanesulfonamide (DMSO-d₆) 2.38 (s, 3H) 3.02 (s, 3H) 3.57 (s, 3 H)7.24 (dd, J = 7.83, 1.77 Hz, 1H) 7.34 (d, J = 1.52 Hz, 1H) 7.38 (d, J =7.83 Hz, 1H) 7.50 (s, 1H) 7.53-7.58 (m, 2H) 7.67-7.72 (m, 1H) 8.30-8.36(m, 1H) 9.18 343 (s, 1H)

Example 18:N-benzyl-2-methoxy-5-(2-methyl-1-oxoisoquinolin-4-yl)benzamide Step 1:N-benzyl-5-bromo-2-methoxybenzamide

To an icebath cooled mixture of 5-bromo-2-methoxybenzoic acid (439 mg,1.9 mmol) in 1:1 CH₂Cl₂:DMF (4 mL) was added benzylamine (0.228 mL, 2.1mmol), EDCI (438 mg, 2.3 mmol), HOBt (311 mg, 2.3 mmol) and NEtiPr₂(0.496 mL, 2.85 mmol). The mixture was then stirred at room temp untilthe rxn was complete. Extractive work-up with EtOAc, washing with satdaq NaHCO₃, H₂O, satd aq KHSO₄, and brine gave the title compound (550mg) after isolation which was carried forward without purification. LCMS(M+H)⁺: 320, 322.

Step 2:N-benzyl-2-methoxy-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide

For about 3 min, N₂ was bubbled through a mixture of the title compoundof N-benzyl-5-bromo-2-methoxybenzamide (174 mg, 0.54 mmol),4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(166 mg, 0.65 mmol), potassium acetate (159 mg, 1.62 mmol) andPd(dppf)Cl₂ (20 mg, 0.03 mmol) in anhydrous DMF (4.2 mL). After heatingat 90° C. for about 2 hr under N₂, silica gel chromatography, elutingwith 0-40% EA in hexane over 7 min and continuing 40% isocratic EA gavethe title compound (138 mg, 0.38 mmol) as a white solid in 70% yield.LCMS (M+H)⁺: 368.

Step 3: N-benzyl-2-methoxy-5-(2-methyl-1-oxoisoquinolin-4-yl)benzamide

For about 3 min, N₂ was bubbled through a mixture ofN-benzyl-2-methoxy-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (51mg, 0.14 mmol), 4-bromo-2-methylisoquinolin-1 (2H)-one (30 mg, 0.13mmol), aq 1M K₃PO₄ (0.3 mL) and Pd(dppf)Cl₂ (10 mg, 0.013 mmol) indioxane (1.15 mL) which was then microwaved at 100° C. for 1 hr. Work-upsimilar to Example 15 and purification by silica gel chromatography,eluting with 5-50% EA in hexane over 4 min and continuing 50% isocraticEA gave the title compound (37 mg, 0.14 mmol) as a tan solid in 71%yield. ¹H NMR (400 MHz, DMSO-d₆) δ 3.57 (s, 3H), 3.97 (s, 3H), 4.52 (d,J=6.06 Hz, 2H), 7.21-7.37 (m, 6H), 7.47-7.51 (m, 2H), 7.56 (td, J=5.37,2.15 Hz, 2H), 7.68-7.73 (m, 1H), 7.79 (d, J=2.27 Hz, 1H), 8.33 (d,J=7.83 Hz, 1H), 8.79 (t, J=6.06 Hz, 1H). LCMS (M+H)⁺: 399.

Examples 19-31 in Table 5 were prepared from4-bromo-2-methylisoquinolin-1(2H)-one and the appropriate boronicacid/ester in a manner similar to Example 18, step 3. For Examples 20-26the microwave temp was increased to 120° C. Aniline hydrochlorides wereprepared by treating the aniline with anhydrous HCl in methanol as thefinal step.

TABLE 5

Ex. ¹H NMR MS No. R¹ Name (ppm (d), 400 MHz) (M + H) 19

4-(3,4-dihydro-2H-1,4- benzoxazin-6-yl)-2- methylisoquinolin-1-one(DMSO-d₆) 3.50-3.59 (m, 3H) 4.14-4.19 (m, 2 H) 5.87 (br. s., 1H) 6.51(dd, J = 8.08, 2.02 Hz, 1H) 6.61 (d, J = 2.02 Hz, 1 H) 6.74 (d, J = 8.08Hz, 1H) 7.38 (s, 1H) 7.50-7.55 (m, 1H) 7.58 (d, J = 7.83 293 Hz, 1H)7.66-7.72 (m, 1H) 8.30 (d, J = 8.08 Hz, 1H) 20

2-methyl-4-(2-oxo-1,3- dihydroindol-6-yl) isoquinolin-1-one (DMSO-d₆)3.55 (s, 2H) 3.56 (s, 3 H) 6.85 (s, 1H) 7.00 (dd, J = 7.58, 1.52 Hz, 1H)7.32 (d, J = 7.58 Hz, 1H) 7.49 (s, 1H) 7.53-7.58 (m, 2H) 7.67-7.72 (m,1H) 8.31-8.35 (m, 1H) 10.47 (s, 1H) 291 21

3-(2-methyl-1- oxoisoquinolin-4-yl) benzenesulfonamide (DMSO-d₆) 3.59(s, 3H) 7.43 (s, 2H) 7.48 (d, J = 8.08 Hz, 1H) 7.56- 7.61 (m, 2H)7.67-7.75 (m, 3H) 7.87-7.92 (m, 2H) 8.36 (d, J = 8.08 Hz, 1H) 315 22

N-(2-hydroxyethyl)-3-(2- methyl-1-oxoisoquinolin-4-yl)benzenesulfonamide (DMSO-d₆) 2.85 (q, J = 6.06 Hz, 2H) 3.39 (q, J =6.06 Hz, 2H) 3.59 (s, 3H) 4.70 (t, J = 5.56 Hz, 1H) 7.47 (d, J = 8.08Hz, 1H) 7.56-7.59 (m, 1H) 7.61 (s, 1H) 7.66-7.77 (m, 4H) 7.83-7.88 (m,2H) 8.36 359 (d, J = 8.08 Hz, 1H) 23

4-(5-amino-2- fluorophenyl)-2- methylisoquinolin-1-one hydrochloride(DMSO-d₆) 3.57 (s, 3H partially obscured) 7.08-7.22 (m, 2H) 7.24 (d, J =9.60 Hz, 1H) 7.32 (t, J = 9.09 Hz, 1H) 7.54-7.60 (m, 2H) 7.67- 7.73 (m,1H) 8.32 (d, J = 7.83 Hz, 1H) 269 24

4-(5-amino-2,4- difluorophenyl)-2- methylisoquinolin-1-one hydrochloride(DMSO-d₆) 3.55 (s, 3H) 6.83 (dd, J = 9.73, 7.96 Hz, 1H) 7.19-7.28 (m,2H) 7.51-7.58 (m, 2H) 7.67- 7.72 (m, 1H) 8.30 (d, J = 8.08 Hz, 1H) 28725

4-(3-amino-5- fluorophenyl)-2- methylisoquinolin-1-one hydrochloride(DMSO-d₆) 3.55 (s, 3 H) 6.47- 6.56 (m, 2H) 6.59 (s, 1 H) 7.51 (s, 1H)7.52-7.62 (m, 2H) 7.69-7.75 (m, 1H) 8.32 (d, J = 8.08 Hz, 1H) 269 26

4-(3-amino-4- fluorophenyl)-2- methylisoquinolin-1-one hydrochloride(DMSO-d₆) 3.55 (s, 3H) 6.64 (d, J = 2.53 Hz, 1H) 6.89 (dd, J = 8.59,2.02 Hz, 1H) 7.13 (dd, J = 11.49, 8.21 Hz, 1H) 7.45 (s, 1 H) 7.52- 7.58(m, 2H) 7.67-7.74 (m, 1H) 8.32 (d, J = 7.07 Hz, 1H) 269 27

N-benzyl-3-(2-methyl-1- oxoisoquinolin-4-yl) benzenesulfonamide(DMSO-d₆) 3.59 (s, 3H) 4.08 (d, J = 6.06 Hz, 2H) 7.17-7.29 (m, 5H) 7.40(d, J = 7.83 Hz, 1H) 7.54 (s, 1H) 7.58 (t, J = 7.58 Hz, 1H) 7.68- 7.76(m, 3H) 7.80 (s, 1H) 7.85 (td, J = 4.48, 1.89 Hz, 1H) 8.26 (t, 405 J =6.32 Hz, 1H) 8.35 (d, J = 8.08 Hz, 1H) 28

N-[3-(2-methyl-1- oxoisoquinolin-4-yl) phenyl]propane-1- sulfonamide(DMSO-d₆) 0.96 (t, J = 7.45 Hz, 3H) 1.72 (sxt, J = 7.48 Hz, 2H)3.10-3.15 (m, 2 H) 3.57 (s, 3H) 7.16 (d, J = 7.58 Hz, 1H) 7.26-7.30 (m,2H) 7.43-7.59 (m, 4 H) 7.68- 7.73 (m, 1H) 8.34 (d, J = 7.83 Hz, 357 1H)9.91 (s, 1H) 29

N-[3-(2-methyl-1- oxoisoquinolin-4-yl) phenyl]butane-1- sulfonamide(DMSO-d₆) 0.84 (t, J = 7.33 Hz, 3H) 1.37 (sxt, J = 7.38 Hz, 2H) 1.67(dt, J = 15.35, 7.61 Hz, 2H) 3.10-3.18 (m, 2H) 3.57 (s, 3H) 7.16 (d, J =7.58 Hz, 1H) 7.24-7.33 (m, 2H) 7.41-7.60 (m, 4H) 7.64- 371 7.74 (m, 1H)8.34 (d, J = 8.08 Hz, 1H) 9.91 (s, 1H) 30

N-[2-methoxy-5-(2-methyl- 1-oxoisoquinolin-4-yl)phenyl]methanesulfonamide (DMSO-d₆) 3.00 (s, 3H) 3.57 (s, 3 H) 3.90 (s,3H) 7.18-7.23 (m, 1H) 7.24-7.30 (m, 1H) 7.33 (d, J = 2.27 Hz, 1H) 7.47(s, 1H) 7.55 (dd, J = 7.58, 5.05 Hz, 2 H) 7.65-7.73 (m, 1H) 8.31-8.37(m, 1H) 9.04 359 (s, 1H) 31

tert-butyl N-methyl-N- [3-(2-methyl-1- oxoisoquinolin-4-yl)phenyl]carbamate (DMSO-d₆) 1.41 (s, 9H) 3.24 (s, 3H) 3.57 (s, 3H) 7.25(d, J = 7.33 Hz, 1H) 7.32-7.38 (m, 2H) 7.44- 7.60 (m, 4H) 7.67-7.73 (m,1H) 8.34 (d, J = 7.83 Hz, 1H) 365

Example 32: 2-methyl-4-[3-(methylamino)phenyl]isoquinolin-1-onehydrochloride

To the title compound of Example 31 (48 mg, 0.13 mmol) was added 4 M HClin dioxane (3 mL). After stirring about 1 hr, the volatile componentswere removed under vacuum. Hexane was added and evaporated (×2). Theresulting white solid was dried under vacuum to give the title compound(39 mg, 0.13 mmol) in quantitative yield. ¹H NMR (400 MHz, DMSO-d₆): δppm 2.85 (s, 3H), 3.57 (s, 3H), 7.10 (br. s., 3H), 7.44 (br. s., 1H),7.51-7.60 (m, 3H), 7.68-7.74 (m, 1H), 8.34 (d, J=7.58 Hz, 1H). LCMS(M+H)⁺: 265.

Example 33:N-methyl-N-[3-(2-methyl-1-oxoisoquinolin-4-yl)phenyl]methanesulfonamide

To the title compound of Example 32 (35 mg, 0.12 mmol) in anhydrousCH₂Cl₂ (0.3 mL), pyridine (0.1 mL) and NEtiPr₂ (0.021 mL, 0.12 mmol) wasadded methanesulfonyl chloride (0.011 mL, 0.14 mmol). After 0.5-1 hr,ice was added to the mixture followed by H₂O and EtOAc. Extractivework-up, washing with H₂O, a 1:1 aq satd KHSO₄:H₂O, and brine, andpurification on silica gel eluting with 35-80% EA in hexane over 6 minand continuing 80% isocratic EA gave the title compound (22 mg, 0.06mmol) as a cream solid in 54% yield. ¹H NMR (400 MHz, DMSO-d₆): δ ppm3.00 (s, 3H), 3.30 (s, 3H), 3.58 (s, 3H), 7.40 (d, J=7.58 Hz, 1H),7.45-7.61 (m, 6H), 7.71 (td, J=7.58, 1.26 Hz, 1H), 8.34 (dd, J=8.21,1.14 Hz, 1H). LCMS (M+H)⁺: 343.

Examples 34-40 in Table 6 were prepared in one step by sulfonylation ofthe aniline Examples 23-26 from Table 5 using methanesulfonyl chloridein a manner similar to Example 33 (one step from the indicated ExampleNo.) or in two steps from 4-bromo-2-methylisoquinolin-1(2H)-one and theappropriate aniline boronic acid/ester in a manner similar to Example 23followed by sulfonylation of the aniline with methanesulfonyl chloridein a manner similar to Example 33 (two steps).

TABLE 6

Ex. No. of steps ¹H NMR MS No. R¹ Name (from Ex. No.) (ppm (d), 400 MHz)(M + H) 34

N-[4-fluoro-3-(2-methyl-1- oxoisoquinolin-4-yl)phenyl]methanesulfonamide 1 step (from Ex. 23) ¹H NMR (400 MHz, DMSO-d₆) d ppm3.04 (s, 3 H) 3.57 (s, 3H) 7.22-7.27 (m, 2H) 7.30-7.40 (m, 2H) 7.53-7.59(m, 347 1H) 7.61 (s, 1H) 7.66- 7.74 (m, 1H) 8.32 (d, J = 8.08 Hz, 1H)9.83 (s, 1H) 35

N-[2,4-difluoro-5-(2-methyl- 1-oxoisoquinolin-4-yl)phenyl]methanesulfonamide 1 step (from Ex. 24) ¹H NMR (400 MHz, DMSO-d₆)d ppm 3.08 (s, 3H) 3.57 (s, 3H) 7.24 (d, J = 8.08 Hz, 1H) 7.45 (t, J =8.21 Hz, 1H) 7.53- 365 7.60 (m, 2H) 7.62 (s, 1H) 7.70 (t, J = 7.58 Hz,1H) 8.32 (d, J = 7.83 Hz, 1H) 9.70 (s, 1H) 36

N-[3-fluoro-5-(2-methyl-1- oxoisoquinolin-4-yl)phenyl]methanesulfonamide 1 step (from Ex. 25) ¹H NMR (400 MHz, DMSO-d₆) d ppm3.12 (s, 3H) 3.57 (s, 3H) 7.01-7.13 (m, 3H) 7.54-7.63 (m, 3H) 7.70-7.77(m, 1H) 8.33 (d, J = 8.08 Hz, 1H) 10.16 (s, 1H) 347 37

N-[2-fluoro-5-(2-methyl-1- oxoisoquinolin-4-yl)phenyl]methanesulfonamide 1 step (from Ex. 26) ¹H NMR (400 MHz, DMSO-d₆) d ppm3.09 (s, 3H) 3.57 (s, 3H) 7.28-7.36 (m, 1H) 7.39-7.48 (m, 2H) 7.49-7.60(m, 347 3H) 7.67-7.74 (m, 1H) 8.34 (d, J = 8.08 Hz, 1H) 9.75 (s, 1H) 38

N-[4-chloro-3-(2-methyl-1- oxoisoquinolin-4-yl)phenyl]methanesulfonamide 2 steps ¹H NMR (400 MHz, DMSO-d₆) d ppm 3.08 (s, 3H)3.56 (s, 3H) 7.07 (d, J = 7.83 Hz, 1H) 7.23 (d, J = 2.78 Hz, 1H) 7.33363, 365 (dd, J = 8.72, 2.65 Hz, 1H) 7.51-7.62 (m, 3H) 7.64-7.70 (m, 1H)8.28-8.36 (m, 1H) 10.04 (s, 1H) 39

N-[4-methyl-3-(2-methyl-1- oxoisoquinolin-4-yl)phenyl]methanesulfonamide 2 steps ¹H NMR (400 MHz, DMSO-d₆) d ppm 2.01(s, 3H) 3.00 (s, 3H) 3.56 (s, 3H) 7.02 (d, J = 8.08 Hz, 1H) 7.06 (d, J =2.53 Hz, 343 1H) 7.22 (dd, J = 8.21, 2.40 Hz, 1H) 7.33 (d, J = 8.34 Hz,1H) 7.45 (s, 1H) 7.51-7.56 (m, 1H) 7.63-7.68 (m, 1H) 8.32 (d, J = 8.08Hz, 1H) 9.71 (s, 1H) 40

N-[3-(2-methyl-1- oxoisoquinolin-4-yl)-5- (trifluoromethyl)phenyl]methanesulfonamide 2 steps ¹H NMR (400 MHz, DMSO-d₆) d ppm 3.14 (s, 3H)3.58 (s, 3H) 7.49-7.52 (m, 2 H) 7.54-7.61 (m, 3H) 7.64 (s, 1H) 7.70-7.76(m, 1H) 8.35 (d, J = 8.08 Hz, 1H) 10.29 397 (s, 1H)

Example 41:N-[4-fluoro-3-[2-methyl-6-(1-methylpyrazol-4-yl)-1-oxoisoquinolin-4-yl]phenyl]methanesulfonamideStep 1: 2-methyl-6-(1-methylpyrazol-4-yl)isoquinolin-1-one

A mixture of 6-bromo-2-methylisoquinolin-1-one (3.8 g, 16 mmol),1-methyl-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (6.69 g, 32mmol), CsF (7.29 g, 48 mmol), Pd(PPh₃)₂Cl₂ (0.4 g, 1 mmol) indioxane/H₂O (60/10 mL) was stirred at 90° C. for 12 hr under N₂. Themixture was concentrated and the residue was purified by silica gelchromatography (PE:EA=2:1) to give the title compound (3.1 g, 81%) as ayellow solid. ¹H NMR (CDCl₃, 400 MHz): δ 8.40 (d, J=12 Hz, 1H), 7.87 (s,1H), 7.74 (s, 1H), 7.59-7.56 (dt, J₁=4 Hz, J₂=8 Hz, 2H), 7.07 (d, J=4Hz, 1H), 6.48 (d, J=8 Hz, 1H) 3.98 (s, 3H), 3.61 (s, 3H). LCMS: 240.0(M+H)⁺.

Step 2: 4-bromo-2-methyl-6-(1-methylpyrazol-4-yl)isoquinolin-1-one

Bromine (1.8 g, 11.25 mmol) in HOAc (6 mL) was added to the titlecompound of 2-methyl-6-(1-methylpyrazol-4-yl)isoquinolin-1-one (3 g,12.5 mmol) in HOAc (24 mL) at 0° C. The mixture was stirred at 30° C.for 15 min, quenched with H₂O (100 mL), and the resulting yellow solidwas collected by filtration to give the title compound (2.04 g, 56%). ¹HNMR (CDCl₃, 400 MHz): δ 8.42 (d, J=8.4 Hz, 1H), 7.87 (d, J=28.8 Hz, 2H),7.82 (d, J=15.6 Hz, 2H), 7.65 (d, J=8 Hz, 2H), 7.38 (s, 1H), 4.00 (s,3H), 3.61 (s, 3H). LCMS: 318.0 (M+H)⁺.

Step 3:4-(5-amino-2-fluorophenyl)-2-methyl-6-(1-methylpyrazol-4-yl)isoquinolin-1-one

4-Bromo-2-methyl-6-(1-methylpyrazol-4-yl)isoquinolin-1-one (35 mg, 0.11mmol), 4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline(29 mg, 0.12 mmol), Pd(dppf)Cl₂ (8 mg, 0.01 mmol) and aq 1 M K₃PO₄ (0.3mL) in dioxane (1.2 mL) were microwaved at 120° C. for 1.25 hr. Work-upwas similar to that described for Example 18, step 3. Silica gelchromatography, eluting with 100% EA followed by 10% methanol in EA,gave the title compound (25 mg, 0.07 mmol) as a cream solid in 64%yield. LCMS (M+H)⁺: 349.

Step 4:N-[4-fluoro-3-[2-methyl-6-(1-methylpyrazol-4-yl)-1-oxoisoquinolin-4-yl]phenyl]methanesulfonamide

4-(5-Amino-2-fluorophenyl)-2-methyl-6-(1-methylpyrazol-4-yl)isoquinolin-1-one(25 mg, 0.07 mmol) in pyridine (0.1 mL) and anhydrous CH₂Cl₂ (0.3 mL)was treated with methanesulfonyl chloride (0.007 mL, 0.09 mmol) in amanner similar to Example 33. After a similar work-up, silica gelchromatography, eluting with 50-100% EA in hexane over 4 min andcontinuing isocratic 100% EA, gave the title compound (24 mg, 0.06 mmol)as a white solid in 78% yield. ¹H NMR (400 MHz, DMSO-d₆) δ 3.06 (s, 3H),3.56 (s, 3H), 3.85 (s, 3H), 7.22-7.45 (m, 4H), 7.59 (s, 1H), 7.76 (dd,J=8.34, 1.52 Hz, 1H), 7.85 (s, 1H), 8.16 (s, 1H), 8.29 (d, J=8.34 Hz,1H), 9.82 (s, 1H). LCMS (M+H)⁺: 427.

Examples 42-45 in Table 7 were prepared from title compound of Example41, step 2, in one step using the appropriate phenyl boronic acid/esterin a manner similar to Example 18, step 3, (1 step) or in two steps fromthe aniline boronic acid/ester followed sulfonylation of the anilinewith the either methanesulfonyl chloride or ethanesulfonyl chloride in amanner similar to Example 41, steps 3 and 4, (2 steps).

TABLE 7

No. of steps Ex. (from ¹H NMR MS No. R¹ Name Ex. No.) (ppm (d), 400 MHz)(M + H) 42

N-[3-[2-methyl-6-(1- methylpyrazol-4-yl)-1- oxoisoquinolin-4-yl]phenyl]methane- sulfonamide 1 step (DMSO-d₆) 3.07 (s, 3H) 3.56 (s, 3H)3.85 (s, 3H) 7.23 (d, J = 7.83 Hz, 1H) 7.28 (d, J = 8.08 Hz, 1H) 7.34(s, 1H) 7.41-7.54 (m, 2H) 7.66 (s, 1H) 409 7.72-7.80 (m, 1H) 7.86 (s,1H) 8.16 (s, 1H) 8.30 (d, J = 8.34 Hz, 1H) 9.87 (s, 1H) 43

N-[2,4-difluoro-5-[2- methyl-6-(1- methylpyrazol-4-yl)-1-oxoisoquinolin-4- yl]phenyl]methane- sulfonamide 2 steps (DMSO-d₆) 3.10(s, 3H) 3.55 (s, 3H) 3.85 (s, 3H) 7.33 (s, 1H) 7.44-7.63 (m, 3H) 7.77(dd, J = 8.59, 1.52 Hz, 1H) 7.89 (s, 1H) 8.19 (s, 1H) 8.28 (d, 445 J =8.34 Hz, 1H) 9.71 (s, 1H) 44

4-(3-ethylsulfonylphenyl)- 2-methyl-6-(1- methylpyrazol-4-yl)isoquinolin-1-one 1 step (DMSO-d₆) 1.17 (t, J = 7.33 Hz, 3H) 3.40 (q, J= 7.41 Hz, 2H) 3.58 (s, 3H) 3.85 (s, 3H) 7.56 (s, 1H) 7.63 (s, 1H) 7.75-8.00 (m, 6H) 8.16 (s, 1H) 409 8.32 (d, J = 8.34 Hz, 1H) 45

N-[4-chloro-3-[2-methyl- 6-(1-methylpyrazol-4-yl)-1-oxoisoquinolin-4-yl] phenyl]ethanesulfonamide 2 steps (DMSO-d₆)1.14-1.28 (m, 3H) 3.11-3.28 (m, 2H) 3.55 (s, 3H) 3.84 (s, 3H) 7.13 (s,1H) 7.26 (d, J = 2.53 Hz, 1H) 7.36 (dd, J = 8.72, 2.65 Hz, 1H) 457, 4597.54 (s, 1H) 7.61 (d, J = 8.84 Hz, 1H) 7.72- 7.77 (m, 1H) 7.81 (s, 1H)8.12 (s, 1H) 8.28 (d, J = 8.34 Hz, 1H) 10.08 (s, 1H)

Example 46:4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methyl-6-(1-methylpyrazol-4-yl)isoquinolin-1-oneStep 1: 2-bromo-1-(cyclopropylmethoxy)-4-methanesulfonylbenzene

A mixture of 2-bromo-4-methanesulfonylphenol (7.2 g, 29 mmol),(chloromethyl) cyclopropane (4.3 g, 32 mmol) and K₂CO₃ (8 g, 58 mmol) inacetone (80 mL) was stirred at 80° C. for 5 hr. The mixture was quenchedwith H₂O (40 mL). Extractive work-up with EtOAc and purification bypreparative HPLC gave the title compound (2.5 g, 28.6%). ¹H NMR (CDCl₃,400 MHz): δ 8.12 (d, J=2.3 Hz, 1H), 7.84 (dd, J₁=2.3 Hz, J₂=8.7 Hz, 1H),6.97 (d, J=8.8 Hz, 1H), 3.99 (d, J=6.7 Hz, 2H), 3.05 (s, 3H), 1.23-1.43(m, 1H), 0.70 (d, J=7.9 Hz, 2H), 0.44 (d, J=5.4 Hz, 2H).

Step 2:2-methyl-6-(1-methylpyrazol-4-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1-one

A mixture of the title compound of Example 41, step 2 (1.4 g, 4.41mmol),4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(2.24 g, 8.83 mmol), KOAc (1.08 g, 11.08 mmol), Pd(dppf)Cl₂ (100 mg,0.137 mmol) in dioxane (50 mL) was stirred at 90° C. for 12 hr under N₂.Purification by CC on silica gel (PE:EA=3:1) gave the title compound(200 mg, 12%) as a yellow solid. ¹H NMR (CDCl₃, 400 MHz): δ 8.55 (d,J=1.5 Hz, 1H), 8.40 (d, J=8.4 Hz, 1H), 7.90 (s, 1H), 7.71 (d, J=16.8 Hz,2H), 4.00 (s, 3H), 3.63 (s, 3H), 1.40 (s, 12H).

Step 3:4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methyl-6-(1-methylpyrazol-4-yl)isoquinolin-1-one

A mixture of 2-bromo-1-(cyclopropylmethoxy)-4-methanesulfonylbenzene(20.8 mg, 0.068 mmol),2-methyl-6-(1-methylpyrazol-4-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1-one (30 mg, 0.08 mmol), NaHCO₃ (14.28 mg, 0.17 mmol), andPd(dppf)Cl₂ (10 mg, 0.014 mmol) in dioxane (2.0 mL) and H₂O (0.5 mL) wasmicrowaved under N₂ at 100° C. for 30 min. Purification by preparativeHPLC gave the title compound (11 mg, 28%) as a white solid. ¹H NMR(CDCl₃, 400 MHz): δ 8.48 (d, J=8.4 Hz, 1H), 7.98-8.04 (m, 1H), 7.89 (d,J=2.4 Hz, 1H), 7.68 (s, 1H), 7.63 (s, 1H), 7.58-7.62 (m, 1H), 7.19-7.21(m, 1H), 7.11-7.15 (m, 1H), 7.09 (s, 1H), 3.93 (s, 3H), 3.83-3.91 (m,2H), 3.66 (s, 3H), 3.12 (s, 3H), 0.94-1.04 (m, 1H), 0.30-0.40 (m, 2H),0.00-0.12 (m, 2H). LCMS: 464.1 (M+H)⁺.

Example 47:N-[3-(6-fluoro-2-methyl-1-oxoisoquinolin-4-yl)phenyl]methanesulfonamideStep 1: 6-fluoro-2-methylisoquinolin-1-one

Sodium hydride (60% in mineral oil) (211 mg, 5.27 mmol) was added to6-fluoro-1,2-dihydroisoquinolin-1-one (716 mg, 4.39 mmol) in anhydrousDMF (6 mL) cooled in an icebath. The mixture was stirred for about 30min at room temp and methyl iodide (0.328 mL, 5.27 mmol) was addeddropwise. After 1 hr, the rxn was judged to be about 60% complete andadditional methyl iodide (0.2 mL, 3.2 mmol) was added. After about 1 hr,ice and H₂O and EtOAc were added to the mixture. After extractivework-up with EtOAc, the title compound (836 mg) was obtained as a creamsolid and carried on without purification.

Step 2: 4-bromo-6-fluoro-2-methylisoquinolin-1-one

Bromine (232 mg, 1.45 mmol, 0.097 mL) in acetic acid (1.0 mL) was addeddropwise, quickly to 6-fluoro-2-methylisoquinolin-1-one (283 mg, 1.61mmol) in acetic acid (7.0 mL) under N₂ and cooled in an icebath. Theicebath was removed and the thick suspension was stirred for 10 min atroom temp. Ice and H₂O and EtOAc were added. Extractive work-up withEtOAc, washing with aq 0.5N NaOH, H₂O, satd aq KHSO₄ and brine, gave thetitle compound as a cream solid (313 mg) which was carried on withoutpurification.

Step 3:N-[3-(6-fluoro-2-methyl-1-oxoisoquinolin-4-yl)phenyl]methanesulfonamide

For about 3 min N₂ was bubbled through a mixture of4-bromo-6-fluoro-2-methyl-isoquinolin-1-one (41 mg, 0.16 mmol),(3-methanesulfonamidophenyl)boronic acid (38 mg, 0.18 mmol), aq 1M K₃PO₄(0.3 mL) and Pd(dppf)Cl₂ (12 mg, 0.016 mmol) in dioxane (1.2 mL) whichwas then microwaved for 1 hr at 120° C. Work-up was similar to thatdescribed for Example 18, step 3. Purification using silica gelchromatography, eluting with 40-80% EA in hexane over 5 min andcontinuing 80% isocratic EA gave the title compound (28 mg, 0.08 mmol)as a cream solid in a combined yield of 38% over steps 1-3. ¹H NMR (400MHz, DMSO-d₆): δ 3.06 (s, 3H), 3.56 (s, 3H), 7.15-7.22 (m, 2H),7.25-7.31 (m, 2H), 7.41 (td, J=8.65, 2.65 Hz, 1H), 7.45-7.52 (m, 1H),7.61 (s, 1H), 8.40 (dd, J=9.09, 6.06 Hz, 1H), 9.88 (s, 1H). LCMS (M+H)⁺:347.

Examples 48-50 in Table 8 were prepared from title compound of Example47, step 2, in one step using the appropriate phenyl boronic acid/esterin a manner similar to Example 47, step 3 (one step) or in two stepsfrom the appropriate aniline boronic acid/ester in a manner similar toExample 47, step 3 followed by sulfonylation of the aniline with eithermethanesulfonyl chloride or ethanesulfonyl chloride in a manner similarto Example 41, step 4 (two steps).

TABLE 8

No. of Ex. steps (from ¹H NMR MS No. R¹ Name Ex. No.) (ppm (d), 400 MHz)(M + H) 48

3-(6-fluoro-2-methyl- 1-oxoisoquinolin-4-yl) benzenesulfonamide 1(DMSO-d₆) 3.58 (s, 3H) 7.11 (dd, J = 10.61, 2.53 Hz, 1H) 7.41-7.49 (m,3H) 7.65-7.76 (m, 3H) 7.87- 7.93 (m, 2H) 8.42 (dd, J = 8.84, 6.06 Hz,1H) 333 49

N-ethyl-3-(6-fluoro-2- methyl-1- oxoisoquinolin-4-yl) benzenesulfonamide1 (DMSO-d₆) 1.00 (t, J = 7.33 Hz, 3H) 2.81-2.89 (m, 2H) 3.58 (s, 3H)7.09 (dd, J = 10.36, 2.53 Hz, 1H) 7.44 (td, J = 8.65, 2.40 Hz, 1H) 7.65(t, J = 5.68 Hz, 1H) 361 7.69 (s, 1H) 7.72-7.79 (m, 2H) 7.82-7.90 (m,2H) 8.42 (dd, J = 9.09, 6.06 Hz, 1H) 50

N-[4-chloro-3-(6- fluoro-2-methyl-1- oxoisoquinolin-4-yl) phenyl]ethanesulfonamide 2 (DMSO-d₆) 1.22 (t, J = 7.33 Hz, 3H) 3.16-3.24 (m,2H) 3.56 (s, 3H) 6.72 (dd, J = 10.23, 2.40 Hz, 1H) 7.24 (d, J = 2.53 Hz,1H) 7.34 (dd, J = 8.59, 2.78 Hz, 1H) 395, 397 7.40 (td, J = 8.72, 2.53Hz, 1H) 7.60 (d, J = 8.84 Hz, 1H) 7.65 (s, 1H) 8.38 (dd, J = 8.84, 5.81Hz, 1H) 9.86- 10.28 (m, 1H)

Example 51:N-[3-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methanesulfonamideStep 1: 2-methyl-2,7-naphthyridin-1-one

Sodium hydride (2.9 g, 72.5 mmol, 60% in oil) was added in portions to2H-2,7-naphthyridin-1-one (3.5 g, 24.0 mmol) in dry DMF (50 mL) at 0° C.After stirring at 0° C. for 30 min, MeI (17.0 g, 118.7 mmol) was addedand the mixture was stirred for an additional 30 min. Satd aq NH₄Cl (250mL) and EtOAc (100 mL) were added. Extractive work-up with EtOAc andpurification by silica gel chromatography (DCM:MeOH=100:1 to 10:1) gavethe title compound (0.5 g, 13.1%) as a yellow solid. ¹H NMR (CDCl3, 400MHz): δ 9.54 (1H, s), 8.64-8.62 (1H, d, J=5.6 Hz), 7.27-7.26 (1H, d,J=5.2 Hz), 7.22-7.20 (1H, d, J=5.6 Hz), 6.37-6.35 (1H, d, J=7.2 Hz),3.54 (3H, s).

Step 2: 4-bromo-2-methyl-2,7-naphthyridin-1-one

Bromine (1.1 g, 6.87 mmol) in acetic acid (10 mL) was added dropwise to2-methyl-2,7-naphthyridin-1-one (1.1 g, 6.87 mmol) in acetic acid (60mL) at 10-15° C. After stirring at 15° C. for 1 hr, the mixture wasconcentrated under vacuum. Purification by silica gel chromatography(DCM: MeOH=50:1 to 10:1) gave the title compound (0.45 g, 27.4%) as ayellow solid. ¹H NMR (CDCl3, 400 MHz): δ 9.61 (1H, s), 8.86-8.85 (1H, d,J=5.6 Hz), 7.62-7.60 (1H, d, J=5.6 Hz), 7.56 (1H, s), 3.63 (3H, s).

Step 3:N-[3-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methanesulfonamide

A mixture of 4-bromo-2-methyl-2,7-naphthyridin-1-one (50 mg, 0.21 mmol),[3-(methanesulfonamido)phenyl]boronic acid (68 mg, 0.31 mmol),Pd(dppf)Cl₂ (15.3 mg, 0.021 mmol) and aq K₃PO₄ (1 M, 0.3 mL, 0.3 mmol)in dioxane (3 mL) was microwaved at 90° C. for 40 min. Purification bysilica gel chromatography (PE:EA=100:1 to 1:1) followed by preparativeHPLC gave the title compound (48.1 mg, 69.8%) as a white solid. ¹H NMR(400 MHz, Methanol-d₄): δ 9.56 (s, 1H), 8.68 (d, J=6.4 Hz, 1H), 7.96 (s,1H), 7.81 (d, J=6.4 Hz, 1H), 7.51 (t, J=7.6 Hz, 1H), 7.37 (d, J=2.0 Hz,1H), 7.34 (d, J=1.6 Hz, 1H), 7.26 (d, J=7.6 Hz, 1H), 3.71 (s, 3H), 3.03(s, 3H). LCMS: 330.0 (M+H)⁺.

Examples 52-56 in Table 9 were prepared from title compound of Example51, step 2, in one step using the appropriate phenyl boronic acid/esterin a manner similar to Example 51, step 3.

TABLE 9

Ex. ¹H NMR MS No. R¹ Name (ppm (d), 400 MHz) (M + H) 52

N-[3-(2-methyl-1-oxo-2,7- naphthyridin-4-yl)phenyl] ethanesulfonamide 1HNMR (400 MHz, CDCl₃) d 9.71 (s, 1H), 8.72 (d, J = 6.0 Hz, 1 H), 7.48 (t,J = 7.6 Hz, 1H), 7.37 (d, J = 6.0 Hz, 1H), 7.29-7.26 (m, 3H), 7.20 (d, J= 7.6 Hz, 1H), 6.74 (s, 1H), 3.69 (s, 3H), 3.21 (q, J = 7.6 Hz, 2H),1.43 (t, 344 J = 7.6 Hz, 3H) 53

N-ethyl-3-(2-methyl-1- oxo-2,7-naphthyridin-4-yl) benzenesulfonamide 1HNMR (400 MHz, CDCl₃) d 9.72 (s, 1H), 8.73 (d, J = 5.6 Hz, 1H), 7.95 (d,J = 7.2 Hz, 1H), 7.92 (s, 1H), 7.67- 7.62 (m, 2H), 7.33 (s, 1H), 7.30(d, J = 5.6 Hz, 1H), 4.48 (s, 1H), 3.70 (s, 3H), 3.13-3.12 (m, 2H), 1.18(t, J = 7.2 344 Hz, 3H) 54

N-benzyl-2-methoxy-5-(2- methyl-1-oxo-2,7- naphthyridin-4-yl)benzenesulfonamide 1H NMR (400 MHz, CDCl₃) d 9.72 (s, 1H), 8.74 (d, J =5.6 Hz, 1H), 7.93 (s, 1H), 7.54 (dd, J₁ = 8.4 Hz, J₂ = 2.4 Hz, 1H),7.27-7.26 (s, 6H), 7.19 (d, J = 3.2 Hz, 1H) 7.06 (d, J = 8.4 Hz, 1H),5.26 (s, 1H), 4.20 (d, J = 5.2 Hz, 2H), 3.96 (s, 3H), 3.70 (s, 3H) 43655

3-(2-methyl-1-oxo-2,7- naphthyridin-4-yl) benzenesulfonamide 1H NMR (400MHz, DMSO-d₆) d 9.46 (d, J = 9.2 Hz, 1H), 8.73 (d, J = 5.6 Hz, 1H),7.89-7.88 (m, 3H), 7.73- 7.69 (m, 2H), 7.39-7.38 (d, J = 5.2 Hz, 1H),3.60 (s, 3H) 316 56

2-methoxy-5-(2-methyl-1- oxo-2,7-naphthyridin-4-yl) benzenesulfonamide1H NMR (400 MHz, DMSO-d₆) d 9.44 (s, 1H), 8.72 (d, J = 5.6 Hz, 1H), 7.80(s, 1H), 7.77 (d, J = 2.4 Hz, 1H), 7.65-7.63 (dd, J₁ = 8.4 Hz, J₂ = 2.4Hz, 1H), 7.34 (d, J = 8.4 Hz, 1H), 7.33 (d, J = 5.2 Hz, 1H), 3.97 (s,3H), 3.59 (s, 3H) 346

Example 57:N-[4-(2,4-difluorophenoxy)-3-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]ethanesulfonamideStep 1:4-(2,4-difluorophenoxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline

A mixture of 3-bromo-4-(2,4-difluorophenoxy)aniline (300 mg, 1 mmol),4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(518 mg, 2 mmol), KOAc (300 mg, 3 mmol) and Pd(dppf)Cl₂ (73.2 mg, 0.1mmol) in dioxane (6 mL) was microwaved at 100° C. for 2 hr. Purificationby silica gel chromatography (PE:EA=10:1 to 5:1) gave the title compound(200 mg, 56%). LCMS: 348.0 (M+H)⁺.

Step 2:4-[5-amino-2-(2,4-difluorophenoxy)phenyl]-2-methyl-2,7-naphthyridin-1-one

For 5 min, N₂ was bubbled through a mixture of4-(2,4-difluorophenoxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline(64.8 mg, 0.187 mmol), the title compound of Example 51, step 2 (30.0mg, 0.124 mmol), K₂CO₃ (51.6 mg, 0.374 mmol) and Pd(dppf)Cl₂ (18.3 mg,0.025 mmol) in dioxane (2.0 mL) and H₂O (0.2 mL) which was thenmicrowaved at 100° C. for 1 hr. Purification by preparative TLC(DCM:MeOH=20:1, Rf=0.5) gave the title compound (25.0 mg, 53%) as yellowgum. LCMS: 380.0 (M+H)⁺.

Step 3:N-[4-(2,4-difluorophenoxy)-3-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]ethanesulfonamide

Ethanesulfonyl chloride (25.4 mg, 0.198 mmol) was added to4-[5-amino-2-(2,4-difluorophenoxy)phenyl]-2-methyl-2,7-naphthyridin-1-one(25.0 mg, 0.066 mmol) and TEA (20.0 mg, 0.198 mmol) in DCM (5 mL) at 0°C. The mixture was stirred at room temp for 18 hr and then purified bypreparative HPLC to give the title compound (8.5 mg, 27.4%) as yellowgum. ¹H NMR (Methanol-d₄, 400 MHz): δ 9.54 (s, 1H), 8.68 (d, J=4.4 Hz,1H), 8.00 (s, 1H), 7.66 (d, J=8.4 Hz, 1H), 7.38-7.33 (m, 2H), 7.09-6.99(m, 2H), 6.96-6.94 (d, J=8.4 Hz, 1H), 6.91-6.85 (m, 1H), 3.70 (s, 3H),3.15 (q, J=7.6 Hz, 2H), 1.35 (t, J=7.6 Hz, 3H). LCMS: 472.1 (M+H)⁺.

Example 58:N-[3-(7-fluoro-2-methyl-1-oxoisoquinolin-4-yl)phenyl]methanesulfonamideStep 1: 7-fluoro-2-methylisoquinolin-1-one

Under N₂, sodium hydride (710 mg, 29.4 mmol) was added to7-fluoro-2H-isoquinolin-1-one (4 g, 24.55 mmol) in dry DMF (40 mL) at 0°C. After stirring at 0° C. for 20 min, CH₃I (5.2 g, 36.7 mmol) wasadded. The mixture was stirred at 26° C. for 2 hr. Satd aq NH₄Cl (20 mL)was added and after extractive work-up with EtOAc, purification bysilica gel chromatography (PE:EA=10:1) gave the title compound (2.2 g,50%) as an off-white solid. ¹H NMR (CDCl₃, 400 MHz): δ 8.06 (dd, J₁=9.6Hz, J₂=2.8 Hz, 1H), 7.50 (dd, J₁=8.8 Hz, J₂=5.2 Hz, 1H), 7.38-7.36 (m,1H), 7.03 (d, J=7.6 Hz, 1H), 6.48 (d, J=7.2 Hz, 1H), 3.61 (s, 3H). LCMS:178.1 [M+H]⁺.

Step 2: 4-bromo-7-fluoro-2H-isoquinolin-1-one

Bromine (3.8 g, 24 mmol) in acetic acid (6 mL) was added slowly to amixture of 7-fluoro-2-methylisoquinolin-1-one (4 g, 22.4 mmol) in aceticacid (8 mL) at 0° C. After stirring at 26° C. for 2 hr, the mixture waspoured into H₂O (100 mL) and the solid was collected by filtration.Purification by silica gel chromatography (PE:EA=20:1) gave the titlecompound (1.4 g, 44%) as an off-white solid. ¹H NMR (CDCl₃, 400 MHz): δ8.11 (d, J=9.2 Hz, 1H), 7.84 (dd, J₁=9.6 Hz, J₂=4.8 Hz, 1H), 7.49-7.45(m, 1H), 7.34 (s, 1H), 3.62 (3H, s). LCMS: 255.9 [M+H]⁺.

Step 3:N-[3-(7-fluoro-2-methyl-1-oxoisoquinolin-4-yl)phenyl]methanesulfonamide

4-Bromo-7-fluoro-2H-isoquinolin-1-one was treated with[3-(methanesulfonamido)phenyl]boronic acid in a manner similar toExample 51, step 3. Isolation and purification also in a similar mannergave the title compound (18 mg, 26.5%) a white solid. ¹H NMR (400 MHz,CDCl₃): δ 8.17 (dd, J₁=9.2 Hz, J₂=2.8 Hz, 1H), 7.52 (dd, J₁=8.0 Hz,J₂=4.0 Hz 1H), 7.50-7.45 (m, 1H), 7.38-7.32 (m, 1H), 7.31-7.27 (m, 2H),7.26-7.21 (m, 1H), 7.03 (s, 1H), 6.72 (brs, 1H), 3.67 (s, 3H), 3.09 (s,3H). LCMS: 347.0 (M+H)⁺.

Examples 59-64 in Table 10 were prepared from title compound of Example58, step 2 using the appropriate phenyl boronic acid/ester in a mannersimilar to Example 18, step 3.

TABLE 10

Ex. ¹H NMR MS No. R¹ Name (ppm (δ), 400 MHz) (M + H) 59

N-ethyl-3-(7-fluoro-2-methyl- 1-oxoisoquinolin-4-yl) benzenesulfonamide(CDCl₃) 8.17 (dd, J₁ = 9.6 Hz, J₂ = 2.4 Hz, 1H), 7.93-7.92 (m, 2H),7.64-7.63 (s, 2H), 7.46- 7.45 (m, 1H), 7.36-7.35 (m, 1H), 7.06 (s, 1H),4.58 (brs, 1H), 3.14-3.07 (m, 2H), 1.16 (t, J = 7.2 361 Hz, 3H) 60

N-benzyl-5-(7-fluoro-2- methyl-1-oxoisoquinolin-4- yl)-2-methoxybenzenesulfonamide (CDCl₃) δ 8.20 (dd, J₁ = 9.3 Hz, J₂ = 2.8 Hz,1H), 7.96 (d, J = 2.4 Hz, 1H), 7.54 (ddd, J₁ = 8.5 Hz, J₂ = 2.3 Hz, 1H),7.47-7.44 (m, 1H), 7.41-7.36 (m, 1H), 7.30- 7.25 (m, 3H), 7.22-7.20 (m,2H), 453 7.06 (d, J = 8.5 Hz, 1H), 7.04 (s, 1H), 5.34 (t, J = 6.0 Hz,1H), 4.21 (d, J = 6.3 Hz, 2H), 3.97 (s, 3H), 3.70 (s, 3H) 61

3-(7-fluoro-2-methhyl-1- oxoisoquinolin-4-yl) benzenesulfonamide (CDCl₃)7.13 (dd, J₁ = 9.6 Hz, J₂ = 2.8 Hz, 1H), 7.03-7.01 (m, 2H), 6.84-6.82(m, 2H), 6.76- 6.74 (m, 1H), 6.69 (s, 1H), 6.67- 6.66 (m, 1H), 6.58-6.56(m, 2H), 2.71 (s, 3H) 333 62

N-[3-(7-fluoro-2-methyl-1- oxoisoquinolin-4-yl) phenyl]ethanesulfonamide(CDCl₃) 8.17 (dd, J₁ = 9.2 Hz, J₂ = 2.8 Hz, 1H), 7.53 (dd, J₁ = 8.8 Hz,J₂ = 3.6 Hz, 1H), 7.44 (t, J = 8.4 Hz, 1H), 7.28-7.27 (m, 3H), 7.20 (d,J = 7.6 Hz, 1H), 7.03 (s, 1H), 6.79 (s, 1H), 3.67 361 (s, 3H), 3.20 (q,J = 7.2 Hz, 2H), 1.43 (t, J = 7.2 Hz, 3H) 63

4-(3-ethylsulfonylphenyl)-7- fluoro-2-methylisoquinolin- 1-one (CDCl₃)1.15 (t, J = 7.45 Hz, 3H) 3.38 (q, J = 7.41 Hz, 2H) 3.60 (s, 3H)7.52-7.57 (m, 1H) 7.61-7.67 (m, 2H) 7.78-7.87 (m, 2H) 7.91- 8.03 (m, 3H)346 64

5-(7-fluoro-2-methyl-1- oxoisoquinolin-4-yl)-2-methoxybenzenesulfonamide (DMSO-d₆) δ 7.98 (d, J = 7.2 Hz, 1H), 7.74 (s,1H), 7.65-7.61 (m, 2H), 7.51-7.48 (m, 2H), 7.35 (d, J = 8.4 Hz, 1H),7.18 (s, 2H), 3.97 (s, 3H), 3.57 (s, 3H) 363

Example 65: 2-methyl-4-(1-methylpyrazol-4-yl)isoquinolin-1-one

For 3 min, N₂ was bubbled through a mixture of4-bromo-2-methylisoquinolin-1(2H)-one (54 mg, 0.23 mmol),(1-methylpyrazol-4-yl)boronic acid (31 mg, 0.25 mmol), aq 2M Na₂CO₃(0.375 mL) and Pd(dppf)Cl₂ (8 mg, 0.01 mmol) in 1,4-dioxane (1.5 mL)which was then microwaved at 120° C. for 1 hr. Work-up in a mannersimilar to Example 18, step 3, and two successive silica gelchromatographies, eluting with 15-80% EA in hexane over 6 min andcontinuing 80% isocratic EA followed by a second chromatography 15-100%EA in hexane over 6 min and continuing 100% isocratic EA gave the titlecompound (28 mg, 0.12 mmol) as a cream solid in 51% yield. ¹H NMR (400MHz, DMSO-d₆): δ ppm 3.54 (s, 3H) 3.92 (s, 3H) 7.50 (s, 1H) 7.55 (ddd,J=8.02, 5.87, 2.27 Hz, 1H) 7.60-7.64 (m, 1H) 7.70-7.80 (m, 2H) 7.95 (s,1H) 8.31 (d, J=7.83 Hz, 1H). LCMS (M+H)⁺: 240.

Examples 66-71 in Table 11 were prepared from4-bromo-2-methylisoquinolin-1(2H)-one in a similar manner to Example 65using commercially available boronic acids/esters or from commerciallyavailable tin compounds using standard Stille-type coupling conditions.

TABLE 11

Ex. ¹H NMR MS No. R¹ Name (ppm (δ), 400 MHz) (M + H) 66

4-(furan-2-yl)-2- methylisoquinolin-1-one (CHLOROFORM-d) 3.61-3.70 (m,3H) 6.50-6.57 (m, 2H) 7.37 (s, 1H) 7.50-7.58 (m, 2 H) 7.69 (dd, J =8.30, 7.03, 1.46 Hz, 1H) 7.93 (d, J = 8.20 Hz, 1H) 8.51 (dd, J = 8.01,2.26 0.98 Hz, 1H) 67

2-methyl-4-(1,3-oxazol- 2-yl)isoquinolin-1-one (CHLOROFORM-d) 3.72 (s,3H) 7.30 (s, 1H) 7.56-7.61 (m, 1H) 7.74 (s, 1H) 7.79 (ddd, J = 8.40,7.03, 1.37 Hz, 1H) 7.99 (s, 1H) 8.52 (dd, J = 8.01, 0.98 Hz, 1H) 8.93(d, J = 8.40 Hz, 1H) 227 68

2-methyl-4-(1H-pyrazol- 5-yl)isoquinolin-1-one (CHLOROFORM-d) 3.61-3.71(m, 3H) 6.66 (br. s., 1H) 7.34 (s, 1H) 7.57 (t, J = 7.42 Hz, 1H) 7.68(t, J = 7.52 Hz, 1H) 7.76 (d, J = 8.01 Hz, 1H) 7.83 (br. s., 1H) 8.52(d, 226 J = 7.81 Hz, 1H) 69

2-methyl-4-(1- methylimidazol-2-yl) isoquinolin-1-one (METHANOL-d₄) 3.55(s, 3 H) 3.65 (s, 3H) 7.10 (br. s., 1H) 7.17 (br. s., 1H) 7.28 (s, 1H)7.54-7.62 (m, 2H) 7.71 (t, J = 7.61 Hz, 1H) 8.41 (d, J = 8.20 Hz, 1H)240 70

2-methyl-4-pyridin- 2-ylisoquinolin-1-one (METHANOL-d₄) 3.69 (s, 3H)7.48 (d, J = 5.86 Hz, 1H) 7.58 (br. s., 2H) 7.65 (d, J = 7.81 Hz, 1H)7.71 (t, J = 7.22 Hz, 1H) 7.76- 7.80 (m, 1H) 7.98 (t, J = 7.03 Hz, 1H)8.42 (d, J = 7.81 Hz, 1H) 8.68 (d, J = 3.32 Hz, 1H) 237 71

2-methyl-4-pyrimidin- 2-ylisoquinolin-1-one (METHANOL-d₄) 3.73 (s, 3H)7.41 (t, J = 4.88 Hz, 1H) 7.59 (t, J = 7.71 Hz, 1H) 7.76 (t, J = 7.71Hz, 1H) 8.27 (s, 1H) 8.42 (d, J = 8.20 Hz, 1H) 8.82 (d, J = 8.40 Hz, 1H)8.90 (d, J = 4.88 Hz, 2H) 238

Example 72:N-[3-[2-methyl-6-(6-methylpyridin-3-yl)-1-oxoisoquinolin-4-yl]phenyl]ethanesulfonamideStep 1: 2-methyl-6-(6-methylpyridin-3-yl)isoquinolin-1-one

A mixture of 6-bromo-2-methylisoquinolin-1-one (160 mg, 0.67 mmol),(6-methylpyridin-3-yl)boronic acid (166 mg, 0.32 mmol), Pd(dppf)Cl₂ (60mg, 0.08 mmol) and satd aq NaHCO₃ (0.6 mL) in dioxane (6.5 mL) wasmicrowaved at 110° C. for 1.5 hr. Purification using silica gelchromatography (PE:EA=3:1 to 2:3) gave the title compound (160 mg,95.2%) as a yellow solid. LCMS: 251.2 (M+H)⁺.

Step 2: 4-bromo-2-methyl-6-(6-methylpyridin-3-yl)isoquinolin-1-one

Bromine (97 mg, 0.61 mmol) in acetic acid (0.61 mL) was added dropwiseto 2-methyl-6-(6-methylpyridin-3-yl)isoquinolin-1-one (160 mg, 0.64mmol) in acetic acid (6 mL) at 0° C. After stirring at room temp for 17min, H₂O (22 mL) was added and adjusted to pH 7-8 with 1M NaOH.Extractive work-up with EtOAc and purification by silica gelchromato-graphy (PE:EA=2:1-3:2) gave the title compound (135 mg, 64.3%)as a yellow solid. LCMS: 329.0 (M+H)⁺.

Step 3:N-[3-[2-methyl-6-(6-methylpyridin-3-yl)-1-oxoisoquinolin-4-yl]phenyl]ethanesulfonamide

A mixture of 4-bromo-2-methyl-6-(6-methylpyridin-3-yl)isoquinolin-1-one(135 mg, 0.41 mmol), [3-(ethylsulfonylamino)phenyl]boronic acid (141 mg,0.62 mmol), Pd(dppf)Cl₂ (35 mg, 0.05 mmol) and aq 1M K₃PO₄ (1.03 mL) indioxane (6 mL) was microwaved at 100° C. for 1 hr. Purification bysilica gel chromatography (PE:EA=3:1-1:2) followed by preparative HPLCgave the title compound (25 mg, 14.1%) as a white solid. ¹H NMR (CDCl₃,400 MHz): δ 8.74 (d, J=2.0 Hz, 1H), 8.41 (d, J=8.4 Hz, 1H), 7.96 (d,J=8.0 Hz, 1H), 7.86 (d, J=8.8 Hz, 1H), 7.75 (s, 1H), 7.58 (s, 1H), 7.47(t, J=8.0 Hz, 1H), 7.39 (s, 1H), 7.35 (d, J=8.4 Hz, 1H), 7.30 (d, J=8.4Hz, 1H), 7.24 (d, J=8.4 Hz, 1H), 3.59 (s, 3H), 3.59 (s, 3H), 3.15 (q,J=7.2 Hz, 2H), 1.19 (t, J=7.2 Hz, 3H). LCMS: 434.1 (M+H)⁺.

Examples 73-74 in Table 12 were prepared from6-bromo-2-methylisoquinolin-1-one and phenylboronic acid in three stepsin a manner similar to Example 72, steps 1-3. For Example 74,[3-(methanesulfonamido)phenyl]boronic acid was substituted for[3-(ethylsulfonyl-amino)phenyl]boronic acid in step 3.

TABLE 12

Ex. ¹H NMR MS No. R¹ Name (ppm (δ), 400 MHz) (M + H) 73 EthylN-[3-(2-methyl-1-oxo-6- (DMSO-d₆) 9.94 (brs, 1H), 8.41 (d, J = 8.4 Hz,419 phenylisoquinolin-4-yl) 1H), 7.85 (d, J = 8.4 Hz, 1H), 7.74 (s, 1H),phenyl]ethanesulfonamide 7.67 (d, J = 7.6 Hz, 2H), 7.57 (s, 1H), 7.50-7.45 (m, 3H), 7.42 (d, J = 7.6 Hz, 1 H), 7.38 (s, 1H), 7.30 (d, J = 8.0Hz, 1 H), 7.23 (d, J = 7.6 Hz, 1H), 3.59 (s, 3H), 3.14 (q, J = 7.2 Hz,2H), 1.19 (t, J = 7.2 Hz, 3H) 74 Methyl N-[3-(2-methyl-1-oxo-6-(CHLOROFORM-d) 8.60 (d, J = 8.4 Hz, 1H), 405 phenylisoquinolin-4-yl)7.78 (dd, J₁ = 8.4 Hz, J₂ = 1.6 Hz, 1H), 7.72 (d,phenyl]methanesulfonamide J = 1.2 Hz, 1H), 7.60-7.58 (m, 2H), 7.49-7.36(m, 5H), 7.31 (d, J = 7.6 Hz, 1H), 7.26-7.23 (m, 1H), 7.10 (s, 1 H),6.47 (s, 1H), 3.70 (s, 3H), 3.08 (s, 3H)

Example 75:N-[3-(2,6-dimethyl-1-oxoisoquinolin-4-yl)phenyl]ethanesulfonamide Step1: 2,6-dimethylisoquinolin-1-one

A mixture of 6-bromo-2-methylisoquinolin-1-one (200.0 mg, 0.84 mmol),methylboronic acid (251.0 mg, 4.2 mmol), Pd(PPh₃)₄ (93.0 mg, 0.08 mmol),K₂CO₃ (232.0 mg, 1.68 mmol) and H₂O (2 drops) in dioxane (10.0 mL) wasmicrowaved at 120° C. for 1 hr. Purification by silica gelchromatography (PE:EA=5:1) gave the title compound (120.0 mg, 82.8%) asa light yellow solid. LCMS: 174.3 (M+H)+.

Step 2: 4-bromo-2,6-dimethylisoquinolin-1-one

2,6-Dimethylisoquinolin-1-one (120.0 mg, 0.60 mmol) in acetic acid (4mL) was treated with Br₂ (96 mg, 0.6 mmol) in acetic acid (0.6 mL) at 0°C. in a manner similar to Example 72, step 2. Isolation, also in asimilar manner, gave the title compound (145.0 mg, 82.9%) as a whiteyellow solid. ¹H NMR (CDCl₃, 400 MHz): δ 8.33 (d, J=8.0 Hz, 1H), 7.60(s, 1H), 7.37 (d, J=8.0 Hz, 1H), 7.35 (s, 1H), 3.60 (s, 3H), 2.54 (s,3H). LCMS: 252.1 (M+H)⁺.

Step 3:N-[3-(2,6-dimethyl-1-oxoisoquinolin-4-yl)phenyl]ethanesulfonamide

4-Bromo-2,6-dimethylisoquinolin-1-one (75.0 mg, 0.30 mmol),[3-(ethylsulfonylamino)-phenyl]boronic acid (82.0 mg, 0.36 mmol),Pd(dppf)Cl₂ (22 mg, 0.03 mmol) and aq 1M K₃PO₄ (0.75 mL) in dioxane (4mL) were reacted in a manner similar to Example 72, step 3. Isolation,also in a similar manner, gave the title compound (60.0 mg, 48.1%) as awhite solid. ¹H NMR (CDCl₃, 400 MHz): δ 8.42 (d, J=8.4 Hz, 1H), 7.46 (t,J=8.0 Hz, 1H), 7.34 (d, J=8.0 Hz, 1H), 7.29-7.27 (m, 2H), 7.24 (d, J=8.0Hz, 1H), 7.03 (s, 1H), 6.68 (s, 1H), 3.65 (s, 3H), 3.21 (q, J=7.2 Hz,2H), 2.42 (s, 3H), 1.43 (t, J=7.2 Hz, 3H). LCMS: 357.0 (M+H)⁺.

Examples 76-78 in Table 13 were prepared in three steps in a similarmanner to Example 75 steps 1-3. For Examples 76 and 77, ethylboronicacid was substituted for methylboronic acid in step 1. For Examples 77and 78, [3-(methanesulfonamido)phenyl]boronic acid was substituted for[3-(ethylsulfonylamino)phenyl]boronic acid in step 3.

TABLE 13

Ex. 1H NMR MS No. R¹ R² Name (ppm (δ), 400 MHz) (M + H) 76 Ethyl EthylN-[3-(6-ethyl-2-methyl-1- (CDCl₃) 8.41 (d, J = 8.4 Hz, 1H), 7.42 371oxoisoquinolin-4-yl) (t, J = 8.4 Hz, 1H), 7.38 (d, J = 8.4 Hz,phenyl]ethanesulfonamide 1H), 7.29-7.25 (m, 2H), 7.19 (d, J = 7.6 Hz,1H), 7.00 (s, 1H), 6.90 (s, 1H), 3.61 (s, 3H), 3.17 (q, J = 7.6 Hz, 2H),2.67 (q, J = 7.6 Hz, 2H), 1.39 (t, J = 7.6 Hz, 3H), 1.19 (t, J = 7.6 Hz,3H) 77 Ethyl Methyl N-[3-(6-ethyl-2-methyl-1- (CDC₃) 8.45 (d, J = 8.4Hz, 1H), 7.48 357 oxoisoquinolin-4-yl) (t, J = 8.0 Hz, 1H), 7.38 (d, J =8.0 Hz, phenyl]methanesulfonamide 1H), 7.32-7.26 (m, 5H), 7.04 (s, 1H),6.66 (s, 1 H), 3.65 (s, 3 H), 3.10 (s, 3H), 2.70 (q, J = 7.6 Hz, 2H),1.23 (t, J = 7.6 Hz, 3H) 78 Methyl Methyl N-[3-(2,6-dimethyl-1-(DMSO-d₆) 9.88 (brs, 1H), 8.23 (d, 343 oxoisoquinolin-4-yl) J = 8.0 Hz,1H), 7.49-7.45 (m, 2H), phenyl]methanesulfonamide 7.39 (d, J = 8.4 Hz,1H), 7.33 (s, 1H), 7.28-7.24 (m, 2H), 7.19 (d, J = 8.0 Hz, 1H), 3.55 (s,3H), 3.06 (s, 3H), 2.39 (s, 3H)

Example 79:4-(5-ethylsulfonyl-2-methoxyphenyl)-2-methyl-6-(1-methylpyrazol-4-yl)isoquinolin-1-one Step 1: 2-bromo-4-ethylsulfanyl-1-fluorobenzene

To a mixture of 3-bromo-4-fluorobenzenethiol (2.07 g, 10 mmol) and K₂CO₃(4.14 g, 30 mmol) in acetone (20 mL) was added EtI (3.12 g, 20 mmol).The mixture was stirred at room temp for 12 hr, filtered, and thevolatile components were removed under vacuum to give the title compound(2.34 g) as light yellow oil which was carried on without purification.¹H NMR (CDCl₃, 400 MHz): δ 7.54 (dd, J₁=6.4 Hz, J₂=2.4 Hz, 1H),7.26-7.25 (m, 1H), 7.05 (t, J=8.4 Hz, 1H), 2.91 (q, J=7.6 Hz, 2H), 1.30(t, J=7.6 Hz, 3H).

Step 2: 2-bromo-4-ethylsulfonyl-1-fluorobenzene

To 2-bromo-4-ethylsulfanyl-1-fluorobenzene (2.2 g, 9.36 mmol) in DCM (20mL) was added m-CPBA (6.47 g, 37.4 mmol). The mixture was stirred atroom temp for 12 hr. Aq satd Na₂S₂O₃ (100 mL) was added, and extractivework-up with CH₂Cl₂ gave the title compound (1.5 g, 50%) as a yellowsolid which was carried on without purification. ¹H NMR (CDCl₃, 400MHz): δ 8.15 (dd, J₁=6.4 Hz, J₂=2.4 Hz, 1H), 7.88-7.85 (m, 1H), 7.32 (t,J=8.4 Hz, 1H), 3.14 (q, J=7.2 Hz, 2H), 1.31 (t, J=7.6 Hz, 3H).

Step 3: 2-bromo-4-ethylsulfonyl-1-methoxybenzene

A mixture of 2-bromo-4-ethylsulfonyl-1-fluorobenzene (0.6 g, 2.25 mmol)and sodium methoxide (1.2 g, 22.2 mmol) in THF (20 mL) was stirred atroom temp for 18 hr. Water (30 mL) was added and extractive work-up withEtOAc followed by silica gel chromatography (PE:EA=10:1-1:1) gave thetitle compound (0.5 g, 79.4%) as a yellow solid. ¹H NMR (CDCl₃, 400MHz): δ 8.08 (d, J=2.4 Hz, 1H), 7.87-7.84 (dd, J₁=8.6 Hz, J₂=2.4 Hz,1H), 7.04 (d, J=8.8 Hz, 1H), 3.99 (s, 3H), 3.11 (q, J=7.4 Hz, 2H), 1.30(t, J=7.4 Hz, 3H).

Step 4:4-(5-ethylsulfonyl-2-methoxyphenyl)-2-methyl-6-(1-methylpyrazol-4-yl)isoquinolin-1-one

For 5 min N₂ was bubbled into a mixture of2-bromo-4-ethylsulfonyl-1-methoxybenzene (300 mg, 1.07 mmol), the titlecompound of Example 46, step 2 (300 mg, 0.82 mmol), K₃PO₄ (435.6 mg,2.05 mmol) and Pd(dppf)Cl₂ (120.2 mg, 0.16 mmol) in dioxane (8 mL) andH₂O (0.8 mL) which was then microwaved at 110° C. for 30 min.Purification by silica gel chromatography (DCM:MeOH=100:0-20:1) gave thetitle compound (200 mg, 55.7%) as a yellow solid. ¹H NMR (CDCl₃, 400MHz): δ 8.51 (d, J=8.4 Hz, 1H), 8.03 (dd, J₁=8.8 Hz, J₂=2.8 Hz, 1H),7.86 (d, J=2.4 Hz, 1H), 7.72 (s, 1H), 7.64 (s, 1H), 7.63-7.61 (m, 1H),7.19 (d, J=8.8 Hz, 1H), 7.15 (d, J=1.2 Hz, 1H), 7.09 (s, 1H), 3.97 (s,3H), 3.85 (s, 3H), 3.68 (s, 3H), 3.18 (q, J=7.6 Hz, 2H), 1.35 (t, J=7.6Hz, 3H). LCMS: 438.1 (M+H)⁺.

Example 80:4-(5-ethylsulfonyl-2-hydroxyphenyl)-2-methyl-6-(1-methylpyrazol-4-yl)isoquinolin-1-one

At −78° C., a 4 M soln of BBr₃ (2.3 mL, 9.2 mmol) in CH₂Cl₂ was added tothe title compound of Example 79 (200.0 mg, 0.458 mmol) in dry CH₂Cl₂ (8mL). The mixture was refluxed for 18 hr. Extractive work-up with CH₂Cl₂and purification by silica gel chromatography (DCM:MeOH=100:1-20:1) gavethe title compound (70 mg, 36.1%) as a brown solid. ¹H NMR (CDCl₃, 400MHz): δ 8.39 (d, J=8.4 Hz, 1H), 7.99 (s, 1H), 7.87 (dd, J₁=8.8 Hz,J₂=2.4 Hz, 1H), 7.80 (s, 1H), 7.79 (s, 1H), 7.76 (d, J=1.6 Hz, 1H), 7.39(s, 1H), 7.35 (d, J=1.2 Hz, 1H), 7.18 (d, J=8.8 Hz, 1H), 3.91 (s, 3H),3.67 (s, 3H), 3.25 (q, J=7.6 Hz, 2H), 1.27 (t, J=7.6 Hz, 3H). LCMS:424.0 (M+H)⁺.

Example 81:4-(2-ethoxy-5-ethylsulfonylphenyl)-2-methyl-6-(1-methylpyrazol-4-yl)isoquinolin-1-one

A mixture of the title compound of Example 80 (25.0 mg, 0.059 mmol),ethyl iodide (27.7 mg, 0.177 mmol), and K₂CO₃ (24.5 mg, 0.177 mmol) inacetone (2 mL) was stirred at room temp for 18 hr. After CH₂Cl₂extractive work-up, purification by preparative TLC (PE:EA=2:1) gave thetitle compound (15.8 mg, 60%) as a white solid. ¹H NMR (CDCl₃, 400 MHz):δ 8.48 (d, J=8.4 Hz, 1H), 7.97 (dd, J₁=8.4 Hz, J₂=2.4 Hz, 1H), 7.86 (d,J=2.4 Hz, 1H), 7.68 (s, 1H), 7.62 (s, 1H), 7.61 (dd, J₁=8.4 Hz, J₂=1.6Hz, 1H), 7.17 (d, J=1.2 Hz, 1H), 7.15 (d, J=8.4 Hz, 1H), 7.08 (s, 1H),4.3 (q, J=7.2 Hz, 2H), 3.94 (s, 3H), 3.66 (s, 3H), 3.17 (q, J=7.6 Hz,2H), 1.35 (t, J=7.6 Hz, 3H), 1.18 (t, J=7.2 Hz, 3H). LCMS: 452.1 (M+H)⁺.

Examples 82-84 in Table 14, the title compound of Example 80 wasO-alkylated with the appropriate alkyl halide in a similar manner toExample 81. Example 85 in Table 14 was prepared in two steps byO-alkylation with tert-butyl N-(2-bromoethyl)carbamate in a similarmanner to Example 81 followed by deprotection of the the Boc group in amanner similar to Example 32.

TABLE 14

Ex. ¹H NMR MS No. R¹ Name (ppm (δ), 400 MHz) (M + H) 82

4-[2-(cyclopropylmethoxy)-5- ethylsulfonylphenyl]-2-methyl-6-(1-methylpyrazol- 4-yl)isoquinolin-1-one (CDCl₃) 8.51 (d, J =8.4 Hz, 1 H), 7.97 (dd, J₁ = 8.4 Hz, J₂ = 2.4 Hz, 1 H), 7.88 (d, J = 2.8Hz, 1 H), 7.70 (s, 1 H), 7.64 (s, 1 H), 7.62 (dd, J₁ = 8.4 Hz, J₂ = 1.6478 Hz, 1 H), 7.21 (d, J = 1.6 Hz, 1 H), 7.13 (d, J = 8.8 Hz, 1 H), 7.11(s, 1 H), 3.96 (s, 3 H), 3.91-3.86 (m, 2 H), 3.67 (s, 3 H), 3.17 (q, J =7.6 Hz, 2 H), 1.34 (t, J = 7.6 Hz, 3 H), 0.99-0.96 (m, 1 H), 0.38-0.35(m, 2 H), 0.10-0.02 (m, 2 H) 83

4-(5-ethylsulfonyl-2- propoxyphenyl)-2-methyl-6- (1-methylpyrazol-4-yl)isoquinolin-1-one (CDCl₃) 8.51 (d, J = 8.4 Hz, 1 H), 7.97 (dd, J₁ = 8.4Hz, J₂ = 2.4 Hz, 1 H), 7.88 (d, J = 2.8 Hz, 1 H), 7.70 (s, 1 H), 7.64(s, 1 H), 7.62 (dd, J₁ = 8.4 Hz, J₂ = 1.6 466 Hz, 1 H), 7.21 (d, J = 1.6Hz, 1 H), 7.13 (d, J = 8.8 Hz, 1 H), 7.11 (s, 1 H), 3.96 (s, 3 H),3.91-3.86 (m, 2 H), 3.67 (s, 3 H), 3.17 (q, J = 7.6 Hz, 2 H), 1.34 (t, J= 7.6 Hz, 3 H), 0.99-0.96 (m, 1 H), 0.38-0.35 (m, 2 H), 0.10-0.02 (m, 2H) 84

4-[5-ethylsulfonyl-2-(2- hydroxyethoxy)phenyl]-2-methyl-6-(1-methylpyrazol- 4 -yl)isoquinolin-1-one (CDCl₃) 8.51 (d, J =8.4 Hz, 1 H), 7.97 (dd, J₁ = 8.4 Hz, J₂ = 2.4 Hz, 1 H), 7.88 (d, J = 2.8Hz, 1 H), 7.70 (s, 1 H), 7.64 (s, 1 H), 7.62 (dd, J₁ = 8.4 Hz, J₂ = 1.6468 Hz, 1 H), 7.21 (d, J =1.6 Hz, 1 H), 7.13 (d, J = 8.8 Hz, 1 H), 7.11(s, 1 H), 3.96 (s, 3 H), 3.91-3.86 (m, 2 H), 3.67 (s, 3 H), 3.17 (q, J =7.6 Hz, 2 H), 1.34 (t, J = 7.6 Hz, 3 H), 0.99-0.96 (m, 1 H), 0.38-0.35(m, 2 H), 0.10-0.02 (m, 2 H) 85

4-[2-(2-aminoethoxy)-5- ethylsulfonylphenyl]-2-methyl-6-(1-methylpyrazol- 4-yl)isoquinolin-1-one (Methanol-d₄) 8.38 (d,J= 8.4 Hz, 1 H), 8.06 (dd, J₁ = 8.4 Hz, J₂ = 2.4 Hz, 1 H), 8.05 (s, 1H), 7.89 (d, J =2.4 Hz, 1 H), 7.83 (s, 1 H), 7.76 (dd, J₁ = 8.4 Hz, J₂ =1.2 Hz, 1 H), 7.47 (d, J = 8.8 Hz, 1 H), 7.44 (s, 1 H), 7.27 (d, J = 1.2Hz, 1 H), 4.46-4.32 (m, 2 H), 3.92 (s, 3 H), 3.67 (s, 3 H), 3.27 (q, J =7.2 Hz, 2 H), 3.25-3.17 (m, 1 H), 3.04-2.96 (m, 1 H), 1.28 (t, J = 7.2Hz, 3 H)

Example 86:N-[2-fluoro-4-methoxy-5-[2-methyl-6-(1-methylpyrazol-4-yl)-1-oxoisoquinolin-4-yl]phenyl]ethanesulfonamideStep 1: 1-bromo-4-fluoro-2-methoxy-5-nitrobenzene and1-bromo-2-fluoro-4-methoxy-5-nitrobenzene

At 0° C., sodium methoxide (344 mg, 6.3 mmol) in dry MeOH (7 mL) wasadded dropwise to 1-bromo-2,4-difluoro-5-nitrobenzene (1 g, 4.2 mmol) indry MeOH (18 mL). The mixture was stirred at room temp for 10 hr andthen refluxed for 8 hr. After extractive work-up, purification by silicagel chromatography (PE:EA=1:0 to 10:1) gave a mixture of the two titlecompounds (765 mg, 72.9%) in about a 2:1 ratio as a yellow solid. LCMS:249.9 (M+H)⁺.

Step 2: 5-bromo-2-fluoro-4-methoxyaniline

Zinc dust (0.95 g, 14.5 mmol) was added to the mixture of two titlecompounds from step 1 (725 mg, 2.9 mmol) in 2:1 MeOH:satd aq NH₄Cl (10mL) at 0° C. After stirring at room temp for 30 min, extractivework-upwith EtOAc and purification by silica gel chromatography(PE:EA=1:0 to 10:1) gave the title compound (260 mg, 41%) as a yellowsolid free of the corresponding regioisomer. ¹H NMR (400 MHz, DMSO-d₆):δ 7.00 (d, J=9.6 Hz, 1H), 6.94 (d, J=13.2 Hz, 1H), 4.88 (s, 2H), 3.72(s, 3H). LCMS: 219.9 (M+H)⁺.

Step 3: N-(5-bromo-2-fluoro-4-methoxyphenyl)ethanesulfonamide

At 0° C., ethansulfonylchloride (1.4 g, 10.9 mmol) was added dropwise toa soln of 5-bromo-2-fluoro-4-methoxyaniline (3.5 g, 24.0 mmol) inpyridine (1.3 g, 16.4 mmol) and dry CH₂Cl₂ (20 mL). After stirring atroom temp for 10 hr, CH₂Cl₂ extractive work-up and purification bysilica gel chromatography (PE:EA=10:0 to 3:1) gave the title compound(2.5 g, 73.5%) as a yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 7.77 (d,J=8.4 Hz, 1H), 6.73 (d, J=11.6 Hz, 1H), 6.27 (s, 1H), 3.89 (s, 3H), 3.10(q, J=7.6 Hz, 2H), 1.40 (t, J=7.6 Hz, 3H). LCMS: 334.0 (M+Na)⁺.

Step 4:N-[2-fluoro-4-methoxy-5-[2-methyl-6-(1-methylpyrazol-4-yl)-1-oxoisoquinolin-4-yl]phenyl]ethanesulfonamide

A mixture of N-(5-bromo-2-fluoro-4-methoxyphenyl)ethanesulfonamide (63mg, 0.20 mmol), the title compound of Example 46, step 2 (75 mg, 0.21mmol), Pd(dppf)Cl₂ (19 mg, 0.03 mmol) and aq K₃PO₄ (1 M, 0.5 mL, 0.5mmol) in dioxane (3 mL) was microwaved at 100° C. for 1 hr. Purificationby silica gel chromatography (PE:EA=1:1-1:4) followed by preparativeHPLC gave the title compound (25 mg, 26.3%) as a white solid. ¹H NMR(400 MHz, CDCl₃) δ 8.48 (d, J=8.4 Hz, 1H), 7.72 (s, 1H), 7.69 (s, 1H),7.58 (d, J=7.2 Hz, 1H), 7.49 (d, J=9.2 Hz, 1H), 7.25 (s, 1H), 7.04 (s,1H), 6.85 (d, J=12.0 Hz, 1H), 6.37 (s, 1H), 3.94 (s, 3H), 3.75 (s, 3H),3.65 (s, 3H), 3.17 (q, J=7.2 Hz, 2H), 1.46 (t, J=7.2 Hz, 3H). LCMS:471.1 (M+H)⁺.

Example 87:N-[3-(2-methyl-1-oxo-6-pyridin-2-ylisoquinolin-4-yl)phenyl]ethanesulfonamideStep 1:2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1-one

For 5 min N₂ was bubbled through a mixture of6-bromo-2-methylisoquinolin-1-one (0.5 g, 2.1 mmol),4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(0.8 g, 3.1 mmol), Pd(dppf)Cl₂ (153.6 mg, 0.21 mmol) and KOAc (0.51 g,5.2 mmol) in dioxane (5 mL) which was then microwaved at 110° C. for 40min. Purification by silica gel chromatography (PE:EA=20:1-5:1) gave thetitle compound (0.45 g, 75.0%) as yellow gum.

Step 2: 2-methyl-6-pyridin-2-ylisoquinolin-1-one

A mixture of2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1-one(420 mg, 1.47 mmol), 2-bromopyridine (698 mg, 4.42 mmol), Pd(dppf)Cl₂(107 mg, 0.15 mmol) and satd aq NaHCO₃ (3.5 mL) in DMSO (25 mL) wasmicrowaved at 150° C. for 45 min. After extractive work-up with EtOAc,purification by silica gel chromatography (PE:EA=3:1-3:2) gave the titlecompound (160 mg, 46.0%) as a white solid. ¹H NMR (CDCl₃, 400 MHz): δ8.76 (d, J=4.8 Hz, 1H), 8.53 (d, J=8.0 Hz, 1H), 8.20 (d, J=1.2 Hz, 1H),8.07 (dd, J₁=8.4 Hz, J₂=1.6 Hz, 1H), 7.85-7.82 (m, 2H), 7.34-7.30 (m,1H), 7.11 (d, J=7.2 Hz, 1H), 6.6 (d, J=7.2 Hz, 1H), 3.64 (s, 3H). LCMS:237.2 (M+H)⁺.

Step 3: 4-bromo-2-methyl-6-pyridin-2-ylisoquinolin-1-one

At 0° C., bromine (78 mg, 0.49 mmol) in acetic acid (0.3 mL) was addeddropwise to 2-methyl-6-pyridin-2-ylisoquinolin-1-one (115 mg, 0.49 mmol)in acetic acid (20 mL). The mixture was stirred at room temp for 20 min.Extractive work-up with CH₂Cl₂ and purification by silica gelchromatography (PE:EA=5:1-1:1) gave the title compound (73.0 mg, 47.7%)as a yellow solid. ¹H NMR (CDCl₃, 400 MHz): δ 8.79 (d, J=4.4 Hz, 1H),8.55 (d, J=8.4 Hz, 1H), 8.44 (s, 1H), 8.19 (d, J=8.8 Hz, 1H), 7.90 (d,J=8.0 Hz, 1H), 7.85 (t, J=7.2 Hz, 1H), 7.42 (s, 1H), 7.36-7.34 (m, 1H),3.64 (s, 3H). LCMS: 314.9 (M+H)⁺.

Step 4:N-[3-(2-methyl-1-oxo-6-pyridin-2-ylisoquinolin-4-yl)phenyl]ethanesulfonamide

For 5 min, N₂ was bubbled through a mixture of4-bromo-2-methyl-6-pyridin-2-yl-isoquinolin-1-one (48.1 mg, 0.153 mmol),[3-(ethylsulfonylamino)phenyl]boronic acid (35.0 mg, 0.153 mmol),Pd(dppf)Cl₂ (22.3 mg, 0.03 mmol) and aq 1M K₃PO₄ (0.38 mL, 0.38 mmol,1M) in dioxane (5 mL) which was then microwaved at 80° C. for 20 min.Purification by silica gel chromatography (PE:EA=3:1 to 1:2) followed bypreparative HPLC gave the title compound (2.5 mg, 3.9%) as a whitesolid. ¹H NMR (Methanol-d4, 400 MHz): δ 8.69 (d, J=8.4 Hz, 1H), 8.59 (d,J=8.4 Hz, 1H), 8.23 (d, J=1.2 Hz, 1H), 8.15-8.22 (m, 1H), 8.10 (dd,J₁=8.4 Hz, J₂=1.6 Hz, 2H), 7.65-7.62 (m, 1H), 7.50-7.45 (m, 3H),7.38-7.30 (m, 2H), 3.71 (s, 3H), 3.16 (q, J=7.2 Hz, 2H), 1.32 (t, J=7.2Hz, 3H). LCMS: 420.1 (M+H)⁺.

Example 88:4-[4-fluoro-2-methoxy-5-(methylsulfonylmethyl)phenyl]-2-methyl-6-(1-methylpyrazol-4-yl)isoquinolin-1-oneStep 1:4-[4-fluoro-2-methoxy-5-(methylsulfonylmethyl)phenyl]-2-methyl-6-(1-methylpyrazol-4-yl)isoquinolin-1-one

At 0-10° C., Br₂ (24 g, 150 mmol) in acetic acid (100 mL) was addeddrop-wise to a soln of methyl 2-fluoro-4-hydroxybenzoate (25.5 g, 150mmol) in acetic acid (600 mL). The mixture was stirred at room tempovernight. Extractive work-up with EtOAc and purification by silica gelchromatography (100% DCM) gave the title compound (32.0 g, 86.5%) as awhite solid. ¹H NMR (Methanol-d₄, 400 MHz): δ 8.03 (d, J=7.2 Hz, 1H),6.68 (d, J=12.0 Hz, 1H), 3.86 (s, 3H). LCMS: 249.1 (M+H)⁺.

Step 2: 5-methyl 5-bromo-2-fluoro-4-methoxybenzoate

Methyl iodide (10.6 g, 74.9 mmol) was added drop-wise to4-[4-fluoro-2-methoxy-5-(methylsulfonylmethyl)phenyl]-2-methyl-6-(1-methylpyrazol-4-yl)isoquinolin-1-one(6.0 g, 24.1 mmol) and K₂CO₃ (9.98 g, 72.3 mmol) in MeCN (120 mL). Themixture was heated at 80° C. overnight. Extractive work-up with EtOAcand purification by silica gel chromatography (PE:EA=60:1-40:1) gave thetitle compound (5.1 g, 80.4%) as a white solid which was carried onwithout purification. ¹H NMR (CDCl₃, 400 MHz): δ 8.15 (d, J=7.6 Hz, 1H),6.66 (d, J=12.0 Hz, 1H), 3.94 (s, 3H), 3.91 (s, 3H). LCMS: 263.0 (M+H)⁺.

Step 3: (5-bromo-2-fluoro-4-methoxyphenyl)methanol

DIBAL-H (45.6 mL, 1M in toluene) was added drop-wise to a soln of5-methyl 5-bromo-2-fluoro-4-methoxybenzoate (5.0 g, 19.0 mmol) inanhydrous CH₂Cl₂ (300 mL) at −78° C. The mixture was stirred at −78° C.for 3 hr and then quenched with MeOH and H₂O. The mixture was filteredand the filter cake rinsed with CH₂Cl₂. The filtrate was washed withbrine, dried over Na₂SO₄, filtered, and concentrated to give the titlecompound (4.18 g, 94.4%) as a white solid which was carried on withoutpurification. ¹H NMR (DMSO-d₆, 400 MHz): δ 7.59 (d, J=7.6 Hz, 1H), 7.02(d, J=12.4 Hz, 1H), 5.25 (t, J=5.6 Hz, 1H), 4.45 (d, J=5.6 Hz, 2H), 3.84(s, 3H).

Step 4: 1-bromo-5-(bromomethyl)-4-fluoro-2-methoxybenzene

PBr₃ (4.7 g, 17.4 mmol) was added drop-wise to a soln of(5-bromo-2-fluoro-4-methoxyphenyl)methanol (4.1 g, 17.4 mmol) inanhydrous CH₂Cl₂ (40 mL) at 0° C. The mixture was stirred at room tempfor 3 hr and poured into ice water. The pH was adjusted to pH 8 withsatd aq NaHCO₃. Extractive work-up with CH₂Cl₂ gave the title compound(4.9 g, 94.8%) as a white solid which was carried on withoutpurification. ¹H NMR (DMSO-d₆, 400 MHz): δ 7.56 (d, J=8.0 Hz, 1H), 6.65(d, J=11.6 Hz, 1H), 4.46 (s, 2H), 3.89 (s, 3H).

Step 5: 1-bromo-4-fluoro-2-methoxy-5-(methylsulfanylmethyl)benzene

Thiomethoxide (1.19 g, 17.0 mmol) was added to a soln of1-bromo-5-(bromo-methyl)-4-fluoro-2-methoxybenzene (4.9 g, 16.4 mmol) inanhydrous DMF (25 mL) at 0° C. The mixture was stirred at room temp for5 hr, and then poured into H₂O (40 mL). Extractive work-up with EtOAcgave the title compound (4.3 g, 99.0%) as colorless oil which wascarried on without purification. ¹H NMR (CDCl₃, 400 MHz): δ 7.50 (d,J=8.0 Hz, 1H), 6.64 (d, J=11.2 Hz, 1H), 3.88 (s, 3H), 3.63 (s, 2H), 2.04(s, 3H).

Step 6: 1-bromo-4-fluoro-2-methoxy-5-(methylsulfonylmethyl)benzene

Oxone (20.9 g, 34.1 mmol) in H₂O (100 mL) was added drop-wise to a solnof 1-bromo-4-fluoro-2-methoxy-5-(methylsulfanylmethyl)benzene (4.3 g,16.2 mmol) in MeOH (100 mL) at 0° C. The mixture was then stirred atroom temp for 3 hr and then poured into H₂O. Extractive work-up withEtOAc, washing with satd aq Na₂SO₃ (40 mL) and brine, gave a solid thatwas triturated with 1:10 EA:MTBE to give the title compound (4.40 g,93.0%) as a white solid. ¹H NMR (CDCl₃, 400 MHz): δ 7.66 (d, J=8.0 Hz,1H), 6.72 (d, J=11.2 Hz, 1H), 4.22 (s, 2H), 3.92 (s, 3H), 2.83 (s, 3H).LCMS: 318.9 (M+Na)⁺.

Step 7:4-[4-fluoro-2-methoxy-5-(methylsulfonylmethyl)phenyl]-2-methyl-6-(1-methylpyrazol-4-yl)isoquinolin-1-one

1-Bromo-4-fluoro-2-methoxy-5-(methylsulfonylmethyl)benzene (34.0 mg,0.114 mmol), the title compound of Example 46, step 2 (50.0 mg, 0.137mmol), Pd(dppf)Cl₂ (20.0 mg, 0.027 mmol) and 1M aq K₃PO₄ (0.47 mL, 0.47mmol) in dioxane (3.0 mL) were microwaved at 100° C. for 40 min.Preparative HPLC gave the title compound (10.0 mg, 18%) as a lightyellow solid. ¹H NMR (CDCl₃, 400 MHz): δ 8.47 (d, J=8.0 Hz, 1H), 7.74(s, 1H), 7.73 (s, 1H), 7.60 (d, J=8.4 Hz, 1H), 7.42 (d, J=8.4 Hz, 1H),7.27 (s, 1H), 7.05 (s, 1H), 6.85 (d, J=12.0 Hz, 1H), 4.32 (d, J=6.4 Hz,2H), 3.93 (s, 3H), 3.77 (s, 3H), 3.64 (s, 3H), 2.93 (s, 3H). LCMS: 456.1(M+H)+.

Example 89:4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-1-oneStep 1:2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1-one

A suspension of 4-bromo-2-methylisoquinolin-1-one (100 mg, 0.42 mmol),bis(pinacolato)diboron (214 mg, 0.84 mmol), Pd(dppf)Cl₂ (31 mg, 0.04mmol) and potassium acetate (104 mg, 1.05 mmol) in dioxane (2 mL) underN₂ was warmed to 90° C. for 135 min. It was then cooled to room temp anddiluted with EtOAc (8 mL). The mixture was washed with aq satd soln ofNaHCO₃ (8 mL) and brine (8 mL). The organic phase was separated, driedover Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue was purified by normal phase CC (10%-90% EtOAc/Hexanes) to givethe title compound (44 mg, 37%). ¹H NMR (CDCl₃, 400 MHz): δ 8.43 (d,J=7.9 Hz, 1H), 8.40 (dd, J=8.2 Hz, 0.9 Hz, 1H), 7.68 (s, 1H), 7.65 (ddd,J=8.2, 8.2, 1.1 Hz, 1H), 7.46 (t, J=7.5 Hz, 1H), 3.63 (s, 3H), 1.38 (s,12H). LCMS (M+H)⁺: 286.

Step 2:4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one

The title compound was prepared in a manner similar to Example 18, step3, substituting 2-bromo-1-(cyclopropylmethoxy)-4-methylsulfonylbenzenefor 4-bromo-2-methylisoquinolin-1(2H)-one and2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1-onefor N-benzyl-2-methoxy-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide.¹H NMR (DMSO-d6, 400 MHz): δ 0.09 (m, 2H), 0.29 (m, 1H), 0.35 (m, 1H),0.94 (m, 1H), 3.22 (s, 3H), 3.57 (s, 3H), 3.95 (m, 2H), 7.16 (d, J=7.9Hz, 1H), 7.37 (d, J=8.8 Hz, 1H), 7.53 (m, 2H), 7.65 (t, J=7.6 Hz, 1H),7.81 (d, J=2.4 Hz, 1H), 7.97 (dd, J=8.8, 2.4 Hz, 1H), 8.30 (d, J=8.1 Hz,1H). LCMS (M+H)⁺: 384.

Alternatively,4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methyl-isoquinolin-1-onecan be prepared as described below.

Step 1:2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1-one

A mixture of 4-bromo-2-methylisoquinolin-1-one (8.0 g, 33.6 mmol),bis(pinacolato) diboron (17.1 g, 67.2 mmol), KOAc (6.6 g, 67.2 mmol),Pd₂(dba)₃ (3.1 g, 3.36 mmol) and X-Phos (1.6 g, 3.36 mmol) in anhydrousdioxane (200 mL) was stirred at 60° C. for 12 hr. The rxn mixture wasconcentrated and the residue was purified by CC on silica gel(PE:EA=15:1) to give the title compound (6.0 g, 62%) as a solid.

Step 2:4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one

The title compound from Step 1 (5.0 g, 17.5 mmol),2-bromo-1-(cyclopropylmethoxy)-4-methylsulfonylbenzene (6.4 g, 21 mmol),K₃PO₄ (9.3 g, 43.9 mmol) and Pd(dppf)Cl₂ (1.4 g, 1.75 mmol) in adioxane/H₂O (100 mL/10 mL) mixture were stirred at 60° C. for 12 hr. Therxn mixture was concentrated under reduced pressure and the residue waspurified by CC on silica gel (EA:DCM=1:4). Appropriate fractions werecombined and concentrated under reduce pressure. The resultant solid wasrecrystallized from DCM:MTBE (1:1, 50 mL) to give the title compound(4.0 g, 60%) as a white solid. ¹H NMR (CDCl₃, 400 MHz): δ 8.51 (dd,J₁=8.0 Hz, J₂=0.8 Hz, 1H), 7.98 (dd, J₁=8.4 Hz, J₂=2.4 Hz, 1H), 7.86 (d,J=2.4 Hz, 1H), 7.53 (m, 2H), 7.16 (d, J=7.6 Hz, 1H), 7.10 (m, 2H), 3.88(m, 2H), 3.66 (s, 3H), 3.09 (s, 3H), 1.02-0.98 (m, 1H), 0.44-0.38 (m,2H), 0.11-0.09 (m, 2H). LCMS: 384.1 (M+H)⁺.

Example 90:4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-6-fluoro-2-methylisoquinolin-1-oneStep 1:2-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

The title compound was prepared in a manner similar to Example 89, step1, substituting 2-bromo-1-(cyclopropylmethoxy)-4-methylsulfonylbenzenefor 4-bromo-2-methylisoquinolin-1-one. ¹H NMR (CDCl₃, 400 MHz): δ 0.46(m, 2H), 0.60 (m, 2H), 1.24 (m, 1H), 1.35 (s, 12H), 3.02 (s, 3H), 3.97(d, J=6.0, 2H), 6.91 (d, J=8.7 Hz, 1H), 7.92 (dd, J=8.7, 2.5 Hz, 1H),8.15 (d, J=2.4 Hz, 1H). LCMS (M+H)⁺: 353.

Step 2:4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-6-fluoro-2-methyl-isoquinolin-1-one

The title compound was prepared in a manner similar to Example 18, step3, substituting the title compound of Example 47, step 2 for4-bromo-2-methylisoquinolin-1(2H)-one and2-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolanefor N-benzyl-2-methoxy-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide. ¹H NMR (DMSO-d₆, 400 MHz): δ 0.12 (m, 2H), 0.32 (m, 1H), 0.39 (m,1H), 0.99 (m, 1H), 3.22 (s, 3H), 3.56 (s, 3H), 3.97 (m, 2H), 6.82 (dd,J=10.5, 2.4 Hz, 1H), 7.39 (m, 2H), 7.61 (s, 1H), 7.82 (d, J=2.3 Hz, 1H),7.98 (dd, J=8.74, 2.4 Hz, 1H), 8.36 (dd, J=8.9, 6.1 Hz, 1H). LCMS(M+H)⁺: 402.

Example 91:4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-7-fluoro-2-methyl-isoquinolin-1-one

The title compound was prepared in a manner similar to Example 18, step3, substituting the title compound of Example 58, step 2 for4-bromo-2-methylisoquinolin-1(2H)-one and2-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolanefor N-benzyl-2-methoxy-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide.¹H NMR (DMSO-d₆, 400 MHz): δ 0.10 (m, 2H), 0.30 (m, 1H), 0.39 (m, 1H),0.94 (m, 1H), 3.22 (s, 3H), 3.58 (s, 3H), 3.95 (m, 2H), 7.24 (dd, J=9,5.3 Hz, 1H), 7.38 (d, J=8.8 Hz, 1H), 7.54 (s, 1H), 7.56 (m, 1H), 7.81(d, J=2.4 Hz, 1H), 7.96 (m, 2H). LCMS (M+H)⁺: 402.

Example 92:4-[2-(2,4-difluorophenoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one

The title compound was prepared in a manner similar to Example 18, step3, substituting 1-(2-bromo-4-methylsulfonylphenoxy)-2,4-difluorobenzenefor 4-bromo-2-methylisoquinolin-1(2H)-one, and2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1-onefor N-benzyl-2-methoxy-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide.¹H NMR (DMSO-d₆, 400 MHz): δ 3.27 (s, 3H), 3.58 (s, 3H), 7.03 (d, J=9.2Hz, 1H), 7.13 (m, 1H), 7.35 (m, 2H), 7.48 (m, 1H), 7.54 (t, J=7.5, 1H),7.67 (s, 1H), 7.69 (m, 1H), 7.97 (m, 1H), 7.98 (s, 1H), 8.30 (d, J=8.1,1H). LCMS (M+H)⁺: 442.

Example 93:N-[4-(2,4-difluorophenoxy)-3-(2-methyl-1-oxoisoquinolin-4-yl)phenyl]ethanesulfonamide

The title compound was prepared in a manner similar to Example 18, step3, substitutingN-[3-bromo-4-(2,4-difluorophenoxy)phenyl]ethanesulfonamide for4-bromo-2-methylisoquinolin-1(2H)-one and2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1-onefor N-benzyl-2-methoxy-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide.¹H NMR (DMSO-d₆, 400 MHz): δ 1.23 (t, J=7.3 Hz, 3H), 3.13 (q, J=7.8 Hz,2H), 3.53 (s, 3H), 6.95 (m, 2H), 7.09 (m, 1H), 7.28 (m, 3H), 7.51 (m,2H), 7.65 (t, J=6.9 Hz, 1H), 8.26 (d, J=0.8 Hz, 1H), 9.83 (s, 1H). LCMS(M+H)⁺: 471.

Example 94: N-[3-(1-methyl-6-oxopyridin-3-yl)phenyl]methanesulfonamide

A mixture of 5-bromo-1-methylpyridin-2-one (100 mg, 0.532 mmol),[3-(methane-sulfonamido)phenyl]boronic acid (171.1 mg, 0.798 mmol), KOAc(130.0 mg, 1.326 mmol) and Pd(dppf)Cl₂ (38.9 mg, 0.05 mmol) indioxane/H₂O (2 mL/0.5 mL) was stirred at 90° C. for 20 min. The mixturewas concentrated and the residue was purified by CC (PE:EA=1:1) to givethe title compound (30.0 mg, 20%) as a brown solid. ¹H NMR (CDCl₃, 400MHz): δ 7.65-7.60 (dd, J₁=7.6 Hz, J₂=2.4 Hz, 1H), 7.54 (d, J=2.4 Hz,1H), 7.41 (t, J=8.0 Hz, 1H), 7.33 (s, 1H), 7.24 (d, J=7.6 Hz, 1H), 7.17(d, J=7.6 Hz, 1H), 6.86 (brs, 1H), 6.67 (d, J=9.2 Hz, 1H), 3.65 (s, 3H),3.05 (s, 3H). LCMS (M+H)⁺: 279.

Example 95:N-[3-(1,4-dimethyl-6-oxopyridin-3-yl)phenyl]methanesulfonamide Step 1:5-bromo-1,4-dimethylpyridin-2-one

To a soln of 5-bromo-4-methylpyridin-2-ol (1.12 g, 6.0 mmol) inanhydrous THF (20 mL) was added NaH (288.0 mg, 12.0 mmol) and the rxnmixture was stirred at 0° C. for 30 min. Then, methyl iodide (1.7 g,12.0 mmol) was added and stirred at room temp for 3 hr. Satd NH₄Cl (100mL) was added and the resulting mixture was extracted with EtOAc (100mL×3). The combined organic layers were washed with brine (100 mL),dried over anhydrous Na₂SO₄ and concentrated. The residue was purifiedby CC on silica gel (PE:EA=10:1-2:1) to give the title compound (1.0 g,83.3%) as a yellow solid. ¹H NMR (CDCl₃, 400 MHz): δ 7.44 (s, 1H), 6.94(s, 1H), 3.51 (s, 3H), 2.24 (s, 3H). LCMS (M+H)⁺: 202.

Step 2: N-[3-(1-methyl-6-oxopyridin-3-yl)phenyl]methanesulfonamide

5-Bromo-1,4-dimethylpyridin-2-one was treated with[3-(methanesulfonamido)phenyl]boronic acid in a manner similar toExample 94 to give the title compound as a white solid. ¹H NMR (CDCl₃,400 MHz) δ 7.43 (t, J=8.0 Hz, 1H), 7.20 (d, J=8.0 Hz, 1H), 7.16 (s, 1H),7.07 (d, J=7.6 Hz, 1H), 6.71 (s, 1H), 6.69 (s, 1H), 3.67 (s, 3H), 3.07(s, 3H), 2.16 (s, 3H). LCMS (M+H)⁺: 293.

Example 96:N-[3-(1,5-dimethyl-6-oxopyridin-3-yl)phenyl]methanesulfonamide Step 1:5-bromo-1,3-dimethylpyridin-2-one

The title compound of step 1 was prepared in a manner similar to Example95, step 1 using 5-bromo-3-methylpyridin-2-ol instead of5-bromo-4-methylpyridin-2-ol to give 5-bromo-1,3-dimethylpyridin-2-one.¹H NMR (CDCl₃, 400 MHz): 7.30 (d, J=2.0 Hz, 1H), 7.26 (d, J=1.6 Hz, 1H),3.53 (s, 3H), 2.16 (s, 3H). LCMS (M+H)⁺: 202.

Step 2: N-[3-(1,5-dimethyl-6-oxopyridin-3-yl)phenyl]methanesulfonamide

5-Bromo-1,3-dimethylpyridin-2-one was treated with[3-(methanesulfonamido)phenyl]boronic acid in a manner similar toExample 94 to give the title compound as a white solid. ¹H NMR (DMSO-d6,400 MHz): 9.74 (s, 1H), 7.91 (d, J=2.4 Hz, 1H), 7.62 (s, 1H), 7.37 (t,J=7.6 Hz, 1H), 7.32 (s, 1H), 7.29 (d, J=7.6 Hz, 1H), 7.13 (d, J=7.6 Hz,1H), 3.52 (s, 3H), 3.02 (s, 3H), 2.08 (s, 3H). LCMS (M+H)⁺: 293.

Example 97:N-[3-(1,4,5-trimethyl-6-oxopyridin-3-yl)phenyl]methanesulfonamide Step1: 5-bromo-3,4-dimethyl-1H-pyridin-2-one

To a mixture of 5-bromo-3,4-dimethylpyridin-2-amine (0.6 g, 3.0 mmol)and H₂SO₄ (98%, 1.62 mL) and H₂O (18 mL) is added a soln of NaNO₂ (243.6mg, 4.2 mmol) in H₂O (1.6 mL) drop-wise at 0° C. Then, it was stirred at31° C. for 30 min and filtered. The resulting solid is washed with H₂Oto provide the title compound (375.0 mg, 62%) as a white solid. ¹H NMR(CDCl₃, 400 MHz): δ 7.48 (s, 1H), 2.32 (s, 3H), 2.19 (s, 3H). LCMS(M+H)⁺: 202.

Step 2: 5-bromo-1,3,4-trimethylpyridin-2-one

To a soln of 5-bromo-3,4-dimethyl-1H-pyridin-2-one (402.0 mg, 2.0 mmol)in anhydrous THF (20 mL) was added NaH (96.0 mg, 2.4 mmol). Theresulting mixture was stirred at 0° C. for 30 min. Methyl iodide (568.0mg, 4.0 mmol) was added and the rxn was stirred at 32° C. for 3 hr.Then, satd aq NH₄Cl (100 mL) was added and the mixture extracted withEtOAc (100 mL×3). The combined organic layers were washed with brine(100 mL), dried over Na₂SO₄, filtered and concentrated. The residue waspurified by CC on silica gel (PE:EA=10:1-2:1) to give the title compound(350.0 mg, 80%) as a white solid. ¹H NMR (CDCl₃, 400 MHz): δ 7.38 (s,1H), 3.52 (s, 3H), 2.27 (s, 3H), 2.20 (s, 3H). LCMS (M+H)⁺: 216.

Step 3:N-[3-(1,4,5-trimethyl-6-oxopyridin-3-yl)phenyl]methanesulfonamide

5-Bromo-1,3,4-trimethylpyridin-2-one was treated with[3-(methanesulfonamido)phenyl]boronic acid in a manner similar toExample 94 to give the title compound as a white solid. ¹H NMR (CDCl₃,400 MHz): δ 7.42 (s, 1H), 7.39 (t, J=7.6 Hz, 1H), 7.24 (s, 1H), 7.16 (s,1H), 7.08 (s, 1H), 7.05 (d, J=7.6 Hz, 1H), 3.59 (s, 3H), 3.06 (s, 3H),2.19 (s, 3H), 2.06 (s, 3H). LCMS (M+H)⁺: 307.

Example 98:5-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-1-methylpyridin-2-oneStep 1:1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one

A soln of 5-bromo-1-methylpyridin-2-one (200.0 mg, 1.06 mmol),bis(pinacolato)-diboron (410.0 mg, 1.61 mmol), potassium acetate (270mg, 2.67 mmol), Pd (dppf)Cl₂ (80 mg, 0.11 mmol) in dioxane (5 mL) washeated at 100° C. for 2 hr under microwave. The mixture was filtered,washed with H₂O and extracted with EtOAc (20 mL×3). The combinedorganics were dried over Na₂SO₄, filtered and concentrated to give thecrude title compound (59.0 mg, 23.6%). LCMS (M+H)⁺: 236.

Step 2:5-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-1-methylpyridin-2-one

1-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-onewas treated with 2-bromo-1-(cyclopropylmethoxy)-4-methylsulfonylbenzenein a manner similar to Example 94 to give the title compound. ¹H NMR(CDCl₃, 400 MHz): δ 7.86 (dd, J₁=8.8 Hz, J₂=2.4 Hz, 1H), 7.81 (d, J=2.0Hz, 1H), 7.68-765 (m, 2H), 7.03 (d, J=8.4 Hz, 1H), 6.66 (d, J=8.8 Hz,1H), 3.95 (d, J=6.8 Hz, 2H), 3.64 (s, 3H), 3.07 (s, 3H), 1.28-1.25 (m,1H), 0.69-0.65 (m, 2H), 0.34-0.38 (m, 2H). LCMS (M+H)⁺: 334.

Example 99:N-[4-(2,4-difluorophenoxy)-3-(1-methyl-6-oxopyridin-3-yl)phenyl]ethanesulfonamideStep 1: 5-[5-amino-2-(2,4-difluorophenoxy)phenyl]-1-methylpyridin-2-one

A mixture of the title compound of step 1 in Example 57 (100 mg, 0.289mmol), 5-bromo-1-methylpyridin-2-one (45.27 mg, 0.240 mmol), K₃PO₄(127.6 mg, 0.60 mmol) and Pd(dppf)Cl₂ (20 mg, 0.027 mmol) in dioxane/H₂O(4/0.5 mL) was stirred at 100° C. for 40 min under microwave. Themixture was concentrated and the residue was purified by CC on silicagel (PE:EA=1:2) to give the title compound (60 mg, 76%). LCMS (M+H)⁺:328.

Step 2:N-[4-(2,4-difluorophenoxy)-3-(1-methyl-6-oxopyridin-3-yl)phenyl]ethanesulfonamide

To a soln of5-[5-amino-2-(2,4-difluorophenoxy)phenyl]-1-methylpyridin-2-one (30 mg,0.09 mmol) in DCM (4 mL) was added TEA (27.3 mg, 0.27 mmol) and EtSO₂Cl(35.39 mg, 0.27 mmol). The mixture was stirred at 30° C. for 12 hR. H₂O(4 mL) was added and the mixture was extracted with DCM (4 mL×3). Theorganic layer was concentrated and the residue was purified by prep-HPLCto give the title compound (10 mg, 26%) as light yellow gum. ¹H NMR(CDCl₃, 400 MHz): δ 7.68-7.66 (m, 2H), 7.28 (d, J=2.4 Hz, 1H), 7.13-7.10(m, 1H), 7.09 (s, 1H), 7.00-6.92 (m, 2H), 6.84-6.86 (m, 1H), 6.78 (d,J=8.4 Hz, 1H), 6.73 (d, J=9.2 Hz, 1H), 3.65 (s, 3H), 3.14 (q, J=7.2 Hz,2H), 1.41 (t, J=7.2 Hz, 3H). LCMS (M+H)⁺: 421.

Example 100:N-[4-(2,4-difluorophenoxy)-3-(1-methyl-6-oxopyridin-3-yl)phenyl]methanesulfonamide

Preparation was carried out in a manner similar to Example 99,substituting methane-sulfonyl chloride for ethanesulfonyl chloride instep 2 to give the title compound as a light yellow gum. ¹H NMR (CDCl₃,400 MHz): δ 7.64-7.62 (m, 2H), 7.29 (d, J=4.8 Hz, 1H), 7.13-7.12 (m,1H), 6.69-6.95 (m, 2H), 6.79 (m, 1H), 6.79 (d, J=8.4 Hz, 1H), 6.62 (d,J=9.4 Hz, 1H), 3.61 (s, 3H), 3.04 (s, 3H). LCMS (M+H)⁺: 407.

Example 101:N-[4-(2,4-difluorophenoxy)-3-(1,4-dimethyl-6-oxopyridin-3-yl)phenyl]methanesulfonamide

Preparation was carried out in a manner similar to Example 100,substituting 5-bromo-1,4-dimethylpyridin-2-one for5-bromo-1-methylpyridin-2-one in step 1 to give the title compound. ¹HNMR (CDCl₃, 400 MHz) δ 7.21-7.16 (m, 4H), 6.95-6.93 (m, 2H), 6.86-6.80(m, 1H), 6.77 (d, J=8.8 Hz, 1H), 6.53 (s, 1H), 3.57 (s, 3H), 3.04 (s,3H), 2.10 (s, 3H). LCMS (M+H)⁺: 421.

Example 102:N-[4-(2,4-difluorophenoxy)-3-(1,5-dimethyl-6-oxopyridin-3-yl)phenyl]methanesulfonamide

Preparation was carried out in a manner similar to Example 100,substituting 5-bromo-1,3-dimethylpyridin-2-one for5-bromo-1-methylpyridin-2-one to give the title compound. ¹H NMR (CDCl₃,400 MHz): δ 7.53 (s, 2H), 7.40 (s, 1H), 7.31 (d, J=2.4 Hz, 1H), 7.17(dd, J₁=8.8 Hz, J₂=2.4 Hz, 1H), 6.99-6.90 (m, 2H), 6.87-6.80 (m, 1H),6.80 (d, J=8.8 Hz, 1H), 3.63 (s, 3H), 3.03 (s, 3H), 2.19 (s, 3H). LCMS(M+H)⁺: 421.

Example 103:N-[4-(2,4-difluorophenoxy)-3-(1,4,5-trimethyl-6-oxopyridin-3-yl)phenyl]methanesulfonamide

Preparation was carried out in a manner similar to Example 100,substituting 5-bromo-1,3,4-trimethylpyridin-2-one for5-bromo-1-methylpyridin-2-one to give the title compound. ¹H NMR(Methanol-d₄, 400 MHz): δ 7.65 (dd, J₁=8.8 Hz, J₂=2.4 Hz, 1H), 7.58 (d,J=2.8 Hz, 1H), 7.39 (s, 1H), 7.05-7.01 (m, 2H), 6.94-6.91 (m, 2H), 3.55(s, 3H), 3.31 (s, 3H), 2.13 (s, 3H), 2.08 (s, 3H). LCMS (M+18+H)⁺: 453.

Example 104: 3-amino-1-methyl-5-(3-methylsulfonylphenyl)pyrazin-2-oneStep 1: 3-amino-5-bromo-1-methylpyrazin-2-one

A soln of 3,5-dibromo-1-methylpyrazin-2-one (500.0 mg, 2.46 mmol),NH₃H₂O (5.0 mL) in dioxane (30.0 mL) was heated at 105° C. for 20 hr.The mixture was concentrated, diluted with EtOAc (50 mL) and filtratedto give the title compound (300.0 mg, 79.0%) which was carried onwithout purification. LCMS (M+H)⁺: 204.

Step 2: 3-amino-1-methyl-5-(3-methylsulfonylphenyl)pyrazin-2-one

A soln of 3-amino-5-bromo-1-methylpyrazin-2-one (81.0 mg, 0.4 mmol),(3-methylsulfonylphenyl)boronic acid (120.0 mg, 0.6 mmol), Cs₂CO₃ (391.0mg, 1.2 mmol), Pd(PPh₃)₄ (20.0 mg, 0.017 mmol) in dioxane (20.0 mL) andH₂O (2.0 mL) was stirred at 95° C. for 12 hr under N₂. The mixture wasconcentrated and purified by silica gel chromatography (PE:EA=3:2) togive the title compound (20.0 mg, 18%). ¹H NMR (DMSO-d₆ 400 MHz): δ 8.35(s, 1H), 8.11 (d, J=8.0 Hz, 1H), 7.80 (d, J=8.0 Hz, 1H), 7.73 (s, 1H),7.66 (t, J=8.0 Hz, 1H), 6.93 (brs, 2H), 3.50 (s, 3H), 3.24 (s, 3H). LCMS(M+H)⁺: 280.

Example 105: 3-amino-5-(3-ethylsulfonylphenyl)-1-methylpyrazin-2-one

Preparation was carried out in a manner similar to Example 104, step 2,substituting (3-ethylsulfonylphenyl)boronic acid for(3-methylsulfonylphenyl)boronic acid to give the title compound. ¹H NMR(DMSO-d₆ 400 MHz): δ 8.30 (t, J=1.6 Hz, 1H), 8.11 (d, J=8.0 Hz, 1H),7.74 (d, J=8.0 Hz, 1H), 7.71 (s, 1H), 7.65 (t, J=8.0 Hz, 1H), 6.90 (brs,2H), 3.48 (s, 3H), 3.29 (q, J=7.2 Hz, 2H), 1.11 (t, J=7.2 Hz, 3H). LCMS(M+H)⁺: 294.

Example 106:N-[5-(6-amino-4-methyl-5-oxopyrazin-2-yl)-2-methoxyphenyl]methanesulfonamide

Preparation was carried out in a manner similar to Example 104, step 2,substituting [3-(methanesulfonamido)-4-methoxyphenyl]boronic acid for(3-methylsulfonylphenyl)boronic acid to give the title compound. ¹H NMR(DMSO-d₆ 400 MHz): δ 8.91 (s, 1H), 7.68 (d, J=2.4 Hz, 1H), 7.61 (dd,J₁=8.8 Hz, J₂=2.4 Hz, 1H), 7.38 (s, 1H), 7.08 (d, J=8.8 Hz, 1H),6.88-6.64 (m, 2H), 3.84 (s, 3H), 3.46 (s, 3H), 2.95 (s, 3H). LCMS(M+H)⁺: 325.

Example 107: 3-amino-1-methyl-5-(3-methylsulfonylphenyl)pyridin-2-one

Preparation was carried out in a manner similar to Example 104, step 2,substituting 3-amino-5-bromo-1-methylpyridin-2-one for3-amino-5-bromo-1-methylpyrazin-2-one to give the title compound. ¹H NMR(Methanol-d₄, 400 MHz): δ 8.06 (t, J=2.0 Hz, 1H), 7.89-7.85 (m, 2H),7.67 (t, J=8.0 Hz, 1H), 7.39 (d, J=2.0 Hz, 1H), 7.03 (d, J=2.4 Hz, 1H),3.67 (s, 3H), 3.17 (s, 3H). LCMS (M+H)⁺: 279.

Example 108: 3-amino-5-(3-ethylsulfonylphenyl)-1-methylpyridin-2-one

Preparation was carried out in a manner similar to Example 105,substituting 3-amino-5-bromo-1-methylpyridin-2-one for3-amino-5-bromo-1-methylpyrazin-2-one to give the title compound. ¹H NMR(Methanol-d4, 400 MHz) δ 8.01 (t, J=2.0 Hz, 1H), 7.88-7.83 (m, 2H), 7.68(t, J=8.0 Hz, 1H), 7.39 (d, J=2.0 Hz, 1H), 7.03 (d, J=2.4 Hz, 1H), 3.67(s, 3H), 3.26 (q, J=7.6 Hz, 2H), 1.25 (t, J=7.6 Hz, 3H). LCMS (M+H)⁺:293.

Example 109:N-[5-(5-amino-1-methyl-6-oxopyridin-3-yl)-2-methoxyphenyl]methanesulfonamide

Preparation was carried out in a manner similar to Example 106,substituting 3-amino-5-bromo-1-methylpyridin-2-one for3-amino-5-bromo-1-methylpyrazin-2-one to give the title compound. ¹H NMR(Methanol-d₄, 400 MHz): δ 7.53 (d, J=2.4 Hz, 1H), 7.34 (dd, J₁=8.8 Hz,J₂=2.4 Hz, 1H), 7.18 (d, J=2.4 Hz, 1H), 7.09 (d, J=8.8 Hz, 1H), 6.96 (d,J=2.4 Hz, 1H), 3.92 (s, 3H), 3.64 (s, 3H), 2.94 (s, 3H). LCMS (M+H)⁺:324.

Example 110:N-[2-methoxy-5-[1-methyl-5-(methylamino)-6-oxopyridin-3-yl]phenyl]methanesulfonamideStep 1: tert-butyl N-(5-bromo-1-methyl-2-oxopyridin-3-yl)carbamate

To a soln of 3-amino-5-bromo-1-methylpyridin-2-one (404.0 mg, 2.0 mmol)in DCM (30 mL) was added (Boc)₂O (654.0 mg, 3.0 mmol), Et₃N (606.0 mg,6.0 mmol) dropwise and DMAP (123.0 mg, 1.0 mmol). The rxn mixture wasstirred for 12 hr at 30° C., quenched with satd aq NH₄Cl (50 mL),extracted with EA (50 mL), dried over Na₂SO₄, filtered and concentrated.Silica gel chromatography (PE:EA=2:1) gave the impure title compound(400.0 mg) as a green solid, which was carried on to the next step. LCMS(M−55)⁺: 247.

Step 2: tert-butylN-(5-bromo-1-methyl-2-oxopyridin-3-yl)-N-methylcarbamate

To a soln of tert-butyl N-(5-bromo-1-methyl-2-oxopyridin-3-yl)carbamate(150.0 mg, impure) in DMF (10 mL) was added NaH (60.0 mg, 1.5 mol, 60%in oil) in portions at 0° C. It was stirred for 30 min. Then CH₃I (231.0mg, 1.5 mmol) was added dropwise at 0° C. The rxn mixture was stirredfor 2 hr at 30° C. The rxn was quenched with satd aq NH₄Cl (15 mL),extracted with EA (20 mL), washed with brine (20 mL), dried over Na₂SO₄,filtered and concentrated to give the title compound (120.0 mg, crude)as a green solid, which was used directly in the next step withoutpurification.

Step 3: 5-bromo-1-methyl-3-(methylamino)pyridin-2-one

To a soln of tert-butylN-(5-bromo-1-methyl-2-oxopyridin-3-yl)-N-methylcarbamate (94.8 mg,crude) in DCM (10 mL) was added HCl/dioxane (1 mL, 4 M) dropwise withstirring at 30° C. The rxn mixture was stirred at 30° C. for 30 min. Themixture was filtered and the filter cake collected. The filtrate wasadjusted to pH 9 with satd aq NaHCO₃, extracted with EtOAc (20 mL),dried over Na₂SO₄, filtered and concentrated to give a green solid whichwas combined with the filter cake to give the title compound (43.2 mg).¹H NMR (CDCl₃ 400 MHz): δ 6.74 (d, J=2.4 Hz, 1H), 6.18 (d, J=2.4 Hz,1H), 5.15 (s, 1H), 3.53 (s, 3H), 2.83 (s, 3H). LCMS (M+H)⁺: 217.

Step 4:N-[2-methoxy-5-[1-methyl-5-(methylamino)-6-oxopyridin-3-yl]phenyl]methanesulfonamide

The title compound was prepared in a manner similar to Example 106,substituting the title compound of step 3 for3-amino-5-bromo-1-methylpyrazin-2-one. ¹H NMR (Methanol-d₄, 400 MHz): δ7.55 (d, J=2.0 Hz, 1H), 7.38 (dd, J₁=8.8, J₂=2.4 Hz, 1H), 7.13-7.08 (m,2H), 6.52 (d, J=2.0 Hz, 1H), 3.93 (s, 3H), 3.63 (s, 3H), 2.94 (s, 3H),2.88 (s, 3H). LCMS (M+H)⁺: 338.

Example 111:N-[5-[5-(ethylamino)-1-methyl-6-oxopyridin-3-yl]-2-methoxyphenyl]methanesulfonamideStep 1: tert-butylN-(5-bromo-1-methyl-2-oxopyridin-3-yl)-N-ethylcarbamate

To a soln of the title compound from Example 110, step 1 (150.0 mg,crude) in DMF (10 mL) was added NaH (60.0 mg, 1.5 mmol, 60% in oil) inportions at 0° C. and stirred for 30 min. Then iodoethane (234.0 mg, 1.5mmol) was added dropwise at 0° C. The rxn mixture was stirred for 2 hrat 30° C. It was then quenched with satd aq NH₄Cl (15 mL), extractedwith EtOAc (20 mL), washed with brine (20 mL), dried over Na₂SO₄,filtered and concentrated to give the title compound (120.0 mg, crude)as a light green solid which was carried forward without purification.

Step 2: 5-bromo-3-(ethylamino)-1-methylpyridin-2-one

To a soln of tert-butylN-(5-bromo-1-methyl-2-oxopyridin-3-yl)-N-ethylcarbamate (99.0 mg, crude)in DCM (10 mL) was added HCl/dioxane (1 mL, 4 M) dropwise with stirringat 30° C. The rxn mixture was stirred for 30 min at 30° C. Then themixture was filtered and the filter cake collected. The filtrate wasadjusted to pH 9 with satd aq NaHCO₃, extracted with EA (20 mL), driedover Na₂SO₄, filtered and concentrated to give a light green solid whichis combined with the filter cake to give the title compound (46.0 mg)which was carried forward without purification. ¹H NMR (CDCl₃ 400 MHz):δ 6.72 (d, J=2.4 Hz, 1H), 6.20 (d, J=1.6 Hz, 1H), 3.51 (s, 3H), 3.09 (q,J=7.2 Hz, 2H), 1.27 (t, J=7.2 Hz, 3H). LCMS (M+H)⁺: 231.

Step 3:N-[5-[5-(ethylamino)-1-methyl-6-oxopyridin-3-yl]-2-methoxyphenyl]methanesulfonamide

The title compound was prepared in a manner similar to Example 106,substituting the title compound of step 2 for3-amino-5-bromo-1-methylpyrazin-2-one. ¹H NMR (CDCl₃ 400 MHz): δ 7.63(d, J=2.0 Hz, 1H), 6.16 (dd, J₁=8.4 Hz, J₁=2.4 Hz, 1H), 6.95 (d, J=8.4Hz, 1H), 6.82-6.80 (m, 1H), 6.39 (d, J=2.4 Hz, 1H), 3.93 (s, 3H), 3.64(s, 3H), 3.19 (q, J=7.2 Hz, 2H), 2.98 (s, 3H), 1.32 (t, J=7.2 Hz, 3H).LCMS (M+H)⁺: 352.

Example 112:N-[5-[5-(cyclopropylmethylamino)-1-methyl-6-oxopyridin-3-yl]-2-methoxyphenyl]methanesulfonamide

To a soln of compound from Example 109 (64.6 mg, 0.2 mmol) in MeOH (3mL) and AcOH (0.3 mL) was added cyclopropanecarbaldehyde (14.0 mg, 0.2mmol) dropwise with stirring at 30° C. NaBH₃CN (24.5 mg, 0.4 mol) wasadded in portions at 30° C. The rxn mixture was stirred for 2 hr at 30°C. It was then quenched with satd aq NH₄Cl (5 mL), extracted with EtOAc(20 mL), dried over Na₂SO₄, filtered and concentrated. The residue waspurified by prep-HPLC to give the title compound (10.0 mg, 13.2%) as alight green solid. ¹H NMR (Methanol-d₄ 400 MHz): δ 7.55 (d, J=2.4 Hz,1H), 7.36 (dd, J=8.4, 2.4 Hz, 1H), 7.16-7.07 (m, 2H), 6.61 (d, J=2.4 Hz,1H), 3.94 (s, 3H), 3.66 (s, 3H), 3.05 (s, 2H), 2.95 (s, 3H), 1.21-1.14(m, 1H), 0.64-0.56 (m, 2H), 0.35-0.28 (m, 2H). LCMS (M+H)⁺: 378.

Example 113:N-[5-[5-(dimethylamino)-1-methyl-6-oxopyridin-3-yl]-2-methoxyphenyl]methanesulfonamide

To a soln of compound from Example 109 (64.6 mg, 0.2 mmol) in MeOH (3mL) and AcOH (0.3 mL) was added HCHO (30.0 mg, 1.0 mmol) dropwise withstirring at 30° C. NaBH₃CN (61 mg, 1.0 mol) was added in portions at 30°C. The rxn mixture was stirred for 2 hr at 30° C. It was then quenchedwith satd aq NH₄Cl (5 mL), extracted with EtOAc (20 mL), dried overNa₂SO₄, filtered and concentrated. The residue was purified by CC onsilica gel (PE:EA=2:3) to give the title compound (30 mg, 43%) as alight green solid. ¹H NMR (Methanol-d₄ 400 MHz): δ 7.54 (d, J=2.4 Hz,1H), 7.47 (d, J=2.4 Hz, 1H), 7.37 (dd, J₁=2.4, J₂=8.4 Hz, 1H), 7.11 (d,J=8.4 Hz, 1H), 7.04 (d, J=2.4 Hz, 1H), 3.93 (s, 3H), 3.63 (s, 3H), 2.94(s, 3H), 2.86 (s, 6H). LCMS (M+H)⁺: 352.

Example 114:N-[5-[5-(diethylamino)-1-methyl-6-oxopyridin-3-yl]-2-methoxyphenyl]methanesulfonamide

The title compound was prepared in a manner similar to Example 113,substituting acetaldehyde for formaldehyde. ¹H NMR (Methanol-d₄ 400MHz): δ 7.55 (d, J=2.4 Hz, 1H), 7.49 (d, J=2.4 Hz, 1H), 7.37 (dd, J₁=8.4Hz, J₂=2.4 Hz, 1H), 7.17-7.11 (m, 1H), 7.06 (d, J=2.4 Hz, 1H), 3.95 (s,3H), 3.65 (s, 3H), 3.34 (m, 4H), 2.97 (s, 3H), 1.11 (t, J=7.2 Hz, 6H).LCMS (M+H)⁺: 380.

Example 115:N-[3-(5-amino-1-methyl-6-oxopyridin-3-yl)-4-(2,4-difluorophenoxy)phenyl]ethanesulfonamideStep 1:3-amino-5-[5-amino-2-(2,4-difluorophenoxy)phenyl]-1-methylpyridin-2-one

The title compound of step 1 was prepared in a manner similar to Example107, substituting the title compound of Example 57, step 1 for(3-methylsulfonylphenyl)boronic acid. LCMS (M+H)⁺: 344.

Step 2:N-[3-(5-amino-1-methyl-6-oxopyridin-3-yl)-4-(2,4-difluorophenoxy)phenyl]ethanesulfonamide

The title compound was prepared in a manner similar to Example 99, step2. ¹H NMR (DMSO-d6, 400 MHz): δ 9.78 (s, 1H), 7.45-7.39 (m, 1H),7.23-7.22 (m, 2H), 7.14 (dd, J₁=7.2 Hz, J₂=1.6 Hz, 1H), 7.10-7.02 (m,2H), 6.85 (d, J=8.8 Hz, 1H), 6.79 (d, J=2.0 Hz, 1H), 3.49 (s, 3H), 3.09(q, J=7.2 Hz, 2H), 1.21 (t, J=7.6 Hz, 3H). LCMS (M+H)⁺: 436.

Example 116:3-amino-5-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-1-methylpyridin-2-one

The title compound was prepared in a manner similar to Example 107,substituting the title compound of Example 90, step 1 for(3-methylsulfonylphenyl)boronic acid. ¹H NMR (CDCl₃, 400 MHz): δ7.84-7.81 (m, 2H), 7.11 (d, J=2.0 Hz, 1H), 7.02 (d, J=2.4 Hz, 1H), 6.84(d, J=2.4 Hz, 1H), 3.95 (d, J=6.8 Hz, 2H), 3.65 (s, 3H), 3.06 (s, 3H),1.31-1.27 (m, 1H), 0.68 (q, J=5.6 Hz, 2H), 0.37 (q, J=5.2 Hz, 2H). LCMS(M+H)⁺: 349.

Example 117: 4-ethoxy-3-(1-methyl-6-oxopyridin-3-yl)benzenesulfonamide

A mixture of the title compound of Example 98, step 1 (40 mg, 0.17mmol), Pd(dppf)Cl₂ (10 mg, 8%) and 3-bromo-4-ethoxybenzene-1-sulfonamide(48 mg, 0.17 mmol) was suspended in 1,4-dioxane (880 μL) and satdbicarbonate soln (aq) (220 μL). The mixture was heated to 95° C. usingmicrowave irradiation (normal) for 60 min. The crude rxn mixture wasfiltered through a short plug of celite, the plug was washed withadditional 1,4-dioxane (1 ml), and the combined filtrate was purified byprep-HPLC. The fractions were combined and lyophilized to give the titlecompound (14 mg, 27%) as a white solid. ¹HNMR (DMSO, 400 MHz): δ 1.33(t, J=6.9, 3H), 3.49 (s, 3H), 4.15 (q, J=6.9, 2H), 6.45 (d, J=9.4 Hz,1H), 7.20-7.23 (m, 3H), 7.64 (dd, J=2.6, 9.4 Hz, 1H), 7.72-7.74 (m, 2H),7.89 (d, J=2.6 Hz, 1H). LCMS (M+H)⁺: 309.

Example 118:4-(2,4-difluorophenoxy)-3-(1-methyl-6-oxopyridin-3-yl)benzenesulfonamideStep 1: 3-bromo-4-fluorobenzenesulfonamide

A soln of 3-bromo-4-fluorobenzenesulfonyl chloride (1 g, 3.3 mmol, 90%pure) stirred at 0° C. in THF (15 ml) and DCM (5 ml) was treated with aqammonium hydroxide (28%) by dropwise addition over 15 min. Afterstirring at 0° C. for 210 min, the mixture was acidified (pH 1) byaddition of 1N HCl (aq). After the mixture was concentrated in vacuo tonear dryness, it was treated with H₂O (50 ml), sonicated for 3 min andfiltered. After the filter cake was washed sequentially with H₂O (50 ml)and hexanes (100 ml), it was dried in vacuo to afford the title compound(503 mg, 60%) as a white solid which was carried forward withoutpurification. LCMS (M−H)⁻: 253.

Step 2: 3-bromo-4-(2,4-difluorophenoxy)benzenesulfonamide

A soln of 3-bromo-4-fluorobenzenesulfonamide (400 mg, 1.6 mmol) and2,4-difluorophenol (228 mg, 1.76 mmol) in DMSO (16 ml) was treated withcesium carbonate (1 g, 3.2 mmol). The resulting mixture was heated to120° C. for 20 min by microwave irridation (normal). The mixture wastreated with H₂O (100 ml) and extracted with EtOAc (3×50 ml). Thecombined organic extracts were washed with satd bicarbonate soln (aq),dried over Na₂SO₄, filtered and concentrated in vacuo to afford a tansolid. The solid was purified by silica gel chromatography (12 g ISCO,30% EtOAc in hexanes 30 ml/min) to give the title compound (340 mg, 58%)as a tan solid. LCMS (M−H)⁻: 362.

Step 3:4-(2,4-difluorophenoxy)-3-(1-methyl-6-oxopyridin-3-yl)benzenesulfonamide

3-Bromo-4-(2,4-difluorophenoxy)benzenesulfonamide (1 eq., 62 mg), thetitle compound of Example 98, step 1 (40 mg, 0.17 mmol), Pd(dppf)Cl₂ (10mg, 8%) in 1,4-dioxane (880 μL) and satd bicarbonate soln (aq) (220 μL)were reacted at 105° C. for 30 min in a manner similar to Example 117.Work-up and preparative HPLC, also in a similar manner, gave the titlecompound (12 mg, 18%) as a white solid. ¹H NMR (DMSO, 400 MHz): δ3.51(s, 3H), 6.49 (d, J=9.4, 1H), 4.15 (q, J=6.9, 2H), 6.45 (d, J=9.4 Hz,1H), 7.20-7.23 (m, 3H), 7.64 (dd, J=2.6, 9.4 Hz, 1H), 7.72-7.74 (m, 2H),7.89 (d, J=2.6 Hz, 1H). LCMS (M+H)⁺: 393.

Example 119:5-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-3-fluoro-1-methylpyridin-2-oneStep 1: 5-bromo-3-fluoro-1-methylpyridin-2-one

A mixture of 5-bromo-3-fluoropyridin-2-ol (1 g, 5.2 mmol), iodomethane(356 mg, 5.7 mmol) and K₂CO₃ (1.4 g, 10.4 mmol) in DMF (10 mL) wasstirred at room temp for 12 hr. The mixture was treated with H₂O (70 ml)and extracted with EtOAc (3×50 ml). The combined organic extracts werewashed with satd bicarbonate soln (aq), dried over Na₂SO₄, filtered andconcentrated in vacuo to afford the title compound (1 g, 93%) as a whitesolid which was carried forward without purification. LCMS (M+H)⁺: 207.

Step 2:3-fluoro-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one

A mixture of 5-bromo-3-fluoro-1-methylpyridin-2-one (1 g, 4.9 mmol),4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(2.5 g, 9.8 mmol), KOAc (1.2 g, 12.3 mmol), and Pd(dppf)Cl₂ (286 mg, 8%)was suspended in 1,4-dioxane (15 mL). After purging the rxn vial with N₂for 5 min, the capped vial was stirred at 80° C. for 1 hr. The mixturewas treated with H₂O (70 ml) and extracted with EtOAc (3×40 ml). Thecombined organic extracts were washed with brine, dried over Na₂SO₄,filtered and concentrated in vacuo to afford a dark residue. The residuewas purified by silica gel chromatography (12 g ISCO, gradient 5% to 75%EtOAc in hexanes) to give the title compound (682 mg, 55%) as a reddishbrown solid.

Step 3:5-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-3-fluoro-1-methylpyridin-2-one

3-Fluoro-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one(40 mg, 0.16 mmol),2-bromo-1-(cyclopropylmethoxy)-4-methanesulfonylbenzene (49 mg, 0.16mmol), and Pd(dppf)Cl₂ (12 mg, 10%) in 1,4-dioxane (880 μL) and satdbicarbonate soln (aq) (220 μL) were reacted, worked up, and purified ina manner similar to Example 117. The title compound (22 mg, 46%) wasobtained as a tan solid. 1H NMR (400 MHz, DMSO-d6): δ 0.31-0.42 (m, 2H)0.53-0.63 (m, 2H) 1.17-1.34 (m, 1H) 3.20 (s, 3H) 3.58 (s, 3H) 3.95-4.06(m, 2H) 7.24-7.33 (m, 1H) 7.72-7.79 (m, 1H) 7.80-7.87 (m, 1H) 7.84 (s,1H) 7.88-7.93 (m, 1H). LCMS (M+H)⁺: 351.

Example 120:5-[2-(2,4-difluorophenoxy)-5-methylsulfonylphenyl]-3-fluoro-1-methylpyridin-2-one

The title compound of Example 119, step 2 (40 mg, 0.16 mmol),1-(2-bromo-4-methylsulfonylphenoxy)-2,4-difluorobenzene (58 mg, 0.16mmol) and Pd(dppf)Cl₂ (12 mg, 10%) in 1,4-dioxane (880 μL) and satdbicarbonate soln (aq) (220 μL) were reacted, worked-up and purified in amanner similar to Example 117. The title compound (26 mg, 46%) wasobtained as a tan solid. ¹H NMR (400 MHz, DMSO-d6)L δ 3.25 (s, 3H) 3.60(s, 3H) 6.91-6.99 (m, 1H) 7.16-7.30 (m, 1H) 7.49-7.62 (m, 2H) 7.76-7.86(m, 2H) 8.00 (m, 2H). LCMS (M+H)⁺: 410.

Example 121:5-[2-(2,4-difluorophenoxy)-5-ethylsulfonylphenyl]-3-fluoro-1-methylpyridin-2-one

The title compound of Example 119, step 2 (40 mg, 0.16 mmol),1-(2-bromo-4-ethylsulfonylphenoxy)-2,4-difluorobenzene (60 mg, 0.16mmol), and Pd(dppf)Cl₂ (12 mg, 10%) in 1,4-dioxane (880 μL) and satdbicarbonate soln (aq) (220 μL) were reacted, worked up and purified in amanner similar to Example 117. The title compound (18 mg, 27%) wasobtained as a tan solid. ¹H NMR (400 MHz, DMSO-d₆): δ 1.13 (t, J=7.33Hz, 3H) 3.34 (q, J=7.33 Hz, 2H) 3.59 (s, 3H) 6.92-6.98 (m, 1H) 7.19-7.27(m, 1H) 7.50-7.61 (m, 2H) 7.76-7.84 (m, 2H) 7.92-7.96 (m, 1H) 7.97-8.01(m, 1H). LCMS (M+H)⁺: 424.

Example 122:N-[4-(2,4-difluorophenoxy)-3-(5-fluoro-1-methyl-6-oxopyridin-3-yl)phenyl]ethanesulfonamideStep 1: N-[3-bromo-4-(2,4-difluorophenoxy)phenyl]ethanesulfonamide

Ethylsulfonyl chloride (177 mg, 1.4 mmol) was added dropwise to astirred soln of 3-bromo-4-(2,4-difluorophenoxy)aniline (328 mg, 1.1mmol) and pyridine (178 μL, 2.2 mmol) in CH₂Cl₂ (2 ml) at 0° C. underN₂. After the mixture warmed to room temp and stirred overnight, it wastreated with 1N HCl (10 ml) and extracted with CH₂Cl₂ (3×10 ml); thecombined organic extracts were washed with satd bicarbonate soln (aq),dried over Na₂SO₄, filtered and concentrated in vacuo to give the titlecompound (430 mg, 99%) as a tan solid which was carried forward withoutpurification. LCMS (M−H)⁻: 391.

Step 2:N-[4-(2,4-difluorophenoxy)-3-(5-fluoro-1-methyl-6-oxopyridin-3-yl)phenyl]ethanesulfonamide

N-[3-Bromo-4-(2,4-difluorophenoxy)phenyl]ethanesulfonamide (77 mg, 0.2mmol), the title compound of Example 119, step 2 (50 mg, 0.2 mmol), andPd(dppf)Cl₂ (14 mg, 10%) in 1,4-dioxane (1 mL) and satd bicarbonate soln(aq) (333 μL) were reacted, worked up and purified in a manner similarto Example 117. The title compound (31 mg, 27%) was obtained as a tansolid. ¹H NMR (400 MHz, DMSO-d₆): δ 1.22 (t, J=7.3, 3H) 3.11 (q, J=7.3Hz, 2H) 3.55 (s, 3H) 6.86 (d, J=8.6 Hz, 1H) 7.02-7.12 (m, 1H) 7.13-7.23(m, 2H) 7.26 (d, J=2.8 Hz, 1H) 7.35-7.52 (m, 1H) 7.60 (m, 1H) 7.79 (s,1H) 9.48-9.96 (m, 1H). LCMS (M+H)⁺: 439.

Example 123:N-[3-(2-methyl-1-oxo-2,6-naphthyridin-4-yl)phenyl]ethanesulfonamide Step1: 4-chloro-2-methyl-2,6-naphthyridin-1-one

N-chlorosuccinimide (0.8 g, 6.2 mmol) was added in portions to a soln of2-methyl-2,6-naphthyridin-1-one (1.0 g, 6.2 mmol) in acetonitrile (25mL), and then heated at 65° C. for 18 hr. Extractive work-up with EtOAcand purification by silica gel chromatography (PE:EA=5:1˜1:1) gave thetitle compound of step 1 (0.6 g, 56%) as a yellow solid. ¹H NMR (CDCl₃,400 MHz): δ 9.29 (s, 1H), 8.81 (d, J=3.6 Hz, 1H), 8.21 (d, J=5.2 Hz,1H), 7.31 (s, 1H), 3.63 (s, 3H). LCMS: 195.0 (M+H)⁺.

Step 2:N-[3-(2-methyl-1-oxo-2,6-naphthyridin-4-yl)phenyl]ethanesulfonamide

A mixture of 4-chloro-2-methyl-2,6-naphthyridin-1-one (50.0 mg, 0.26mmol), [3-(ethylsulfonylamino)phenyl]boronic acid (88.0 mg, 0.38 mmol),Pd(dppf)Cl₂ (15.3 mg, 0.026 mmol) and K₃PO₄ (190 mg, 0.9 mmol) indioxane (3 mL) and H₂O (0.5 mL) was microwaved at 120° C. undermicrowave for 2 hr. Purification by silica gel chromatography on(PE:EA=10:1 to 1:1) followed by preparative HPLC gave the title compound(5.9 mg, 6.8%) as a yellow solid. ¹H NMR (Methanol-d4, 400 MHz): δ 8.99(brs, 1H), 8.71 (d, J=6.0 Hz, 1H), 8.39 (d, J=5.6 Hz, 1H), 7.62 (s, 1H),7.51 (t, J=8.0 Hz, 1H), 7.41-7.40 (m, 1H), 7.36 (dd, J₁=8.0 Hz, J₂=1.2Hz, 1H), 7.29 (d, J=5.6 Hz, 1H), 3.72 (s, 3H), 3.17 (q, J=7.6 Hz, 2H),1.35 (t, J=7.6 Hz, 3H). LCMS: 344.1 (M+H)⁺.

Examples 124-126 in Table 15 were prepared from title compound ofExample 123, step 1, using the appropriate phenyl boronic acid/ester ina manner similar to Example 123, step 2. Example 127 in Table 15 wasprepared in two steps from the title compound of Example 123, step 1,and the title compound of Example 57, step 1, by coupling the anilineboronic ester in a manner similar to Example 123, step 1, except thatthe temp was raised from 120° C. to 150° C. and NMP was used instead ofdioxane (step 1), followed by sulfonylation of the aniline in a mannersimilar to Example 57, step 3 (step 2).

TABLE 15

Ex. ¹H NMR MS No. R¹ Name (ppm (δ , 400 MHz) (M + H) 124

N-ethyl-3-(2-methyl-1-oxo- 2,6-naphthyridin-4-yl) benzenesulfonamide(Methanol-d₄) 8.86 (d, J = 0.8 Hz, 1H), 8.70 (d, J = 5.6 Hz, 1H), 8.28(dd, J₁ = 5.6 Hz, J₂ = 0.8 Hz, 1H), 7.98-7.95 (m, 2H), 7.78-7.75 (m, 2H), 7.60 (s, 1H), 3.71 (s, 3H), 2.98 (q, J = 7.2 Hz, 2H), 1.10 (t, 344 J= 7.2 Hz, 3H) 125

N-[3-(2-methyl-1-oxo-2,6- naphthyridin-4-yl)phenyl] methanesulfonamide(CD₃OD) 8.98 (s, 1H), 8.70 (d, J = 5.2 Hz, 1H), 8.34 (d, J = 5.2 Hz,1H), 7.60 (s, 1H), 7.52 (t, J = 8.0 Hz, 1H), 7.40 (s, 1 H), 7.36 (d, J =8.0 Hz, 1H), 7.31 (d, J = 8.0 Hz, 1H), 3.71 (s, 3H), 3.04 (s, 3H) 330126

4-(3-ethylsulfonylphenyl)- 2-methyl-2,6- naphthyridin-1-one (CD₃OD) 9.02(s, 1H), 8.78 (d, J = 5.2 Hz, 1H), 8.57 (d, J = 5.2 Hz, 1H), 8.09 (s,1H), 8.06 (d, J = 7.6 Hz, 1H), 7.93 (d, J = 7.6 Hz, 1H), 7.85 (t, J =7.6 Hz, 1H), 7.80 (s, 1H), 3.74 (s, 3 H), 3.33 (q, J = 7.6 329 Hz, 2H),1.29 (t, J = 7.6 Hz, 3H) 127

N-[4-(2,4-difluorophenoxy)- 3-(2-methyl-1-oxo-2,6- naphthyridin-4-yl)phenyl]ethanesulfonamide (CD₃OD) 9.02 (s, 1H), 8.78 (d, J = 5.2 Hz, 1H),8.57 (d, J = 5.2 Hz, 1H), 8.09 (s, 1H), 8.06 (d, J = 7.6 Hz, 1H), 7.93(d, J = 7.6 Hz, 1H), 7.85 (t, J = 7.6 Hz, 1H), 7.80 (s, 1H), 3.74 (s,3H), 3.33 (q, J = 7.6 Hz, 2H), 1.29 (t, J = 7.6 Hz, 3H) 472

Example 128:4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methyl-6-(4-methylpyrazol-1-yl)isoquinolin-1-oneStep 1: 2-methyl-6-(4-methylpyrazol-1-yl)isoquinolin-1-one

6-Bromo-2-methylisoquinolin-1-one (300.0 mg, 1.27 mmol),4-methyl-1H-pyrazole (210.0 mg, 2.54 mmol), CuI (30.0 mg, 0.127 mmol)and K₂CO₃ (360.0 mg, 2.54 mmol) in NMP (3.0 mL) were microwaved at 195°C. for 5 hr. Extractive work-up with EtOAc followed by silica gelchromatography (PE:EA=5:1) gave the title compound of step 1 (160.0 mg,52%) as a light yellow solid. ¹H NMR (CDCl₃, 400 MHz): δ 8.49 (d, J=8.8Hz, 1H), 7.84 (s, 1H), 7.83 (d, J=2.0 Hz, 1H), 7.74 (dd, J₁=8.8 Hz,J₂=2.0 Hz, 1H), 7.59 (s, 1H), 7.10 (d, J=7.6 Hz, 1H), 6.52 (d, J=7.6 Hz,1H), 3.62 (s, 3H), 2.19 (s, 3H). LCMS: 240.0 (M+H)⁺.

Step 2: 4-bromo-2-methyl-6-(4-methylpyrazol-1-yl)isoquinolin-1-one

Bromine (94 mg, 0.59 mmol) in acetic acid (2 mL) was added drop-wise toa soln of 2-methyl-6-(4-methylpyrazol-1-yl)isoquinolin-1-one (140.0 mg,0.583 mmol) in acetic acid (4 mL) at 0° C. The mixture was then stirredat room temp for 17 min and quenched with H₂O (10 mL). The pH wasadjusted to about 7-8 with aq 1M NaOH. Extractive work-up with EtOAcfollowed by purification using silica gel chromatography (PE:EA=1:1)gave the title compound of step 2 (120.0 mg, 56%) as a light yellowsolid. ¹H NMR (CDCl₃, 400 MHz): δ 8.51 (d, J=8.8 Hz, 1H), 8.06 (d, J=2.0Hz, 1H), 7.89 (s, 1H), 7.87 (dd, J₁=8.8 Hz, J₂=2.0 Hz, 1H), 7.63 (s,1H), 7.42 (s, 1H), 3.62 (s, 3H), 2.20 (s, 3H). LCMS: 319.8 (M+H)⁺.

Step 3:4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methyl-6-(4-methylpyrazol-1-yl)isoquinolin-1-one

4-Bromo-2-methyl-6-(4-methylpyrazol-1-yl)isoquinolin-1-one (40.0 mg,0.126 mmol), the title compound of Example 90, step 1 (53.2 mg, 0.152mmol), Pd(dppf)Cl₂ (200.0 mg, 0.05 mmol) and aq 1M K₃PO₄ (0.38 mL, 0.38mmol) in dioxane (3 mL) were heat in a microwave at 100° C. for 1 hr.Purification by preparative HPLC gave the title compound (15.0 mg, 25%)as a white solid. ¹H NMR (CDCl₃, 400 MHz): δ 8.57 (d, J=8.4 Hz, 1H),8.00 (d, J=8.4 Hz, 1H), 7.90 (s, 1H), 7.75 (d, J=7.6 Hz, 1H), 7.73 (s,1H), 7.54 (s, 1H), 7.50 (s, 1H), 7.14 (s, 1H), 7.12 (s, J=9.2 Hz, 1H),3.96-3.83 (m, 2H), 3.68 (s, 3H), 3.13 (s, 3H), 2.15 (s, 3H), 1.01-0.94(m, 1H), 0.38-0.28 (m, 2H), 0.08-0.02 (m, 2H). LCMS: 464.1 (M+H)⁺.

Example 129:N-[4-(2,4-difluorophenoxy)-3-(7-methyl-8-oxoimidazo[1,5-a]pyrazin-5-yl)phenyl]ethanesulfonamideStep 1: 5-bromo-7-methylimidazo[1,5-a]pyrazin-8-one

To a soln of 5-bromo-1-methylpyrazin-2-one (500.0 mg, 2.65 mmol) and(p-tolylsulfonyl)methyl isocyanide (573.0 mg, 2.94 mmol) in THF (4 mL)was added a suspension of NaH (235.0 mg, 5.9 mmol) in THF (2 mL) at 0°C. under N₂. After stirring at 0° C. for 30 min, the mixture was stirredat 30° C. for another 1.5 hr. The rxn mixture was quenched with H₂O (20mL) at 0° C., and extracted with EtOAc (30 mL×2). The organic phaseswere combined, washed with brine (30 mL), dried over Na₂SO₄, filteredand evaporated. The crude product was purified by CC (PE:EA=1/1) to givethe title compound (300.0 mg, 50%) as a light yellow solid. ¹H NMR(CDCl₃ 400 MHz): δ 8.06 (d, J=4.4 Hz, 1H), 6.61 (s, 1H), 3.48 (s, 3H).LCMS (M+H)⁺: 228.

Step 2:5-[5-amino-2-(2,4-difluorophenoxy)phenyl]-7-methylimidazo[1,5-a]pyrazin-8-one

A soln of 5-bromo-7-methylimidazo[1,5-a]pyrazin-8-one (114.0 mg, 0.5mmol), the title compound of Example 57, step 1 (208.0 mg, 0.6 mmol),Pd(dppf)₂Cl₂ (37.0 mg, 0.05 mmol), NaHCO₃ (126.0 mg, 1.5 mmol) indioxane (10 mL) and H₂O (1 mL) was stirred in microwave at 110° C. underN₂ for 3 hr. The solvent was evaporated to give the crude product, whichwas purified by CC (PE:EA=3:1) to give the title compound (110 mg, 60%)as a yellow solid. ¹H NMR (CDCl₃ 400 MHz): δ 7.94 (s, 1H), 7.82 (s, 1H),6.93-6.82 (m, 2H), 6.79-6.74 (m, 4H), 6.41 (s, 1H), 3.50 (s, 3H). LCMS(M+H)⁺: 369.

Step 3:N-[4-(2,4-difluorophenoxy)-3-(7-methyl-8-oxoimidazo[1,5-a]pyrazin-5-yl)phenyl]ethanesulfonamide

The title compound was prepared in a manner similar to Example 99, step2, substituting the title compound of step 2 for the title compound ofExample 99, step 1. ¹H NMR (CDCl₃ 400 MHz): δ 8.57 (s, 1H), 8.14 (s,1H), 7.50 (d, J=2.4 Hz, 1H), 7.30 (dd, J₁=8.8 Hz, J₂=2.4, 1H), 7.20-7.16(m, 1H), 6.99-6.87 (m, 2H), 6.83 (s, 1H), 6.55 (d, J=8.8 Hz, 1H), 3.59(s, 3H), 3.13 (q, J=7.2 Hz, 2H), 1.39 (t, J=7.2 Hz, 3H). LCMS (M+H)⁺:461.

Example 130:5-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-7-methylimidazo[1,5-a]pyrazin-8-one

The title compound was prepared in a manner similar to Example 129, step2, substituting2-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolanefor4-(2,4-difluorophenoxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)anilineto give the title compound. ¹H NMR (CDCl₃ 400 MHz): δ 8.08 (dd, J₁=8.8Hz, J₂=2.4, 1H), 8.03 (s, 1H), 7.98 (d, J=2.4 Hz, 1H), 7.58 (s, 1H),7.16 (d, J=8.8 Hz, 1H), 6.50 (s, 1H), 3.97 (d, J=7.2 Hz, 2H), 3.54 (s,3H), 3.11 (s, 3H), 1.15-1.02 (m, 1H), 0.59-0.49 (m, 2H), 0.26-0.17 (m,2H). LCMS (M+H)⁺: 374.

Example 131:7-methyl-5-(3-methylsulfonylphenyl)imidazo[1,5-a]pyrazin-8-one

A soln of compound from Example 129, step 1 (80 mg, 0.35 mmol),(3-methyl-sulfonylphenyl)boronic acid (77 mg, 0.6 mmol), Na₂CO₃ (106 mg,1 mmol), Pd(PPh₃)₂Cl₂ (30.0 mg) in dioxane (3 mL) and H₂O (0.5 mL) wasstirred at 120° C. for 18 hr under N₂. After cooling to room temp, themixture was filtered, concentrated and purified by prep-HPLC to give thetitle compound (20.0 mg, 20%). ¹H NMR (Methanol-d4 400 MHz): δ 8.70-8.65(m, 1H), 8.30-8.20 (m, 2H), 8.16 (d, J=8.0 Hz, 1H), 8.05 (d, J=8.0 Hz,1H), 7.88 (t, J=8.0 Hz, 1H), 7.22 (s, 1H), 3.56 (s, 3H), 3.24 (s, 3H).LCMS (M+H)⁺: 304.

Example 132:N-[2-methoxy-5-(7-methyl-8-oxoimidazo[1,5-a]pyrazin-5-yl)phenyl]methanesulfonamide

The title compound was prepared in a manner similar to Example 131,substituting [3-(methanesulfonamido)-4-methoxyphenyl]boronic acid for(3-methylsulfonylphenyl)boronic acid to give the title compound. ¹H NMR(Methanol-d4 400 MHz): δ 8.81 (s, 1H), 8.29 (s, 1H), 7.70 (s, 1H), 7.50(m, 2H), 7.28 (d, J=8.0 Hz, 1H), 7.12 (s, 1H), 4.01 (s, 3H), 3.56 (s,3H), 3.08 (s, 3H). LCMS (M+H)⁺: 349.

Example 133:5-(3-ethylsulfonylphenyl)-7-methylimidazo[1,5-a]pyrazin-8-one

The title compound was prepared in a manner similar to Example 131,substituting (3-ethylsulfonylphenyl)boronic acid for(3-methylsulfonylphenyl)boronic acid to give the title compound. ¹H NMR(Methanol-d4 400 MHz): δ 8.83 (s, 1H), 8.27 (s, 1H), 8.21 (s, 1H), 8.10(d, J=7.6 Hz, 1H), 8.05 (d, J=8.0 Hz, 1H), 7.89 (t, J=8.0 Hz, 1H), 7.24(s, 1H), 3.56 (s, 3H), 3.31 (q, J=7.6 Hz, 2H), 1.28 (t, J=7.6 Hz, 3H).LCMS (M+H)⁺: 318.

Example 134:N-[3-(5-chloro-1-methyl-6-oxopyridin-3-yl)-4-(2,4-difluorophenoxy)phenyl]ethanesulfonamide

The title compound was prepared in a manner similar to Example 122,substituting3-chloro-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-onefor3-fluoro-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one.LCMS (M+H)⁺: 455.

Example 135:4-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-2-methylisoquinolin-1-one

The title compound was prepared in a manner similar to Example 89,substituting 2-bromo-1-(cyclopropylmethoxy)-4-ethylsulfonylbenzene for2-bromo-1-(cyclopropylmethoxy)-4-methylsulfonylbenzene. LCMS (M+H)⁺:398.

Example 136:6-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2,4-dimethylpyridazin-3-one

The title compound was prepared in a manner similar to Example 90,substituting 6-chloro-2,4-dimethylpyridazin-3-one for4-bromo-6-fluoro-2-methylisoquinolin-1-one. LCMS (M+H)⁺: 349.

Example 137:6-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2,5-dimethylpyridazin-3-one

The title compound was prepared in a manner similar to Example 90,substituting 6-chloro-2,5-dimethylpyridazin-3-one for4-bromo-6-fluoro-2-methylisoquinolin-1-one. LCMS (M+H)⁺: 349.

Example 138:N-[4-(2,4-difluorophenoxy)-3-[1-methyl-6-oxo-5-(trifluoromethyl)pyridine-3-yl]phenyl]ethanesulfonamide

The title compound was prepared in a manner similar to Example 122,substituting1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyridin-2-onefor3-fluoro-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one.LCMS (M+H)⁺489.

Example 139:N-[4-(2,4-difluorophenoxy)-3-(4-fluoro-1-methyl-6-oxopyridin-3-yl)phenyl]ethanesulfonamide

Step 1:2-chloro-5-[2-(2,4-difluorophenoxy)-5-nitrophenyl]-4-fluoropyridine

A mixture of2-chloro-4-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(170 mg, 0.66 mmol), 2-bromo-1-(2,4-difluorophenoxy)-4-nitrobenzene (326mg, 0.98 mmol), Pd₂(dba)₃ (30 mg, 5%), and tricyclohexylphosphine (280mg, 10%) was suspended in 1,4-dioxane (4 mL) and aq 1M K₃PO₄ (2 mL). Themixture was heated to 70° C. using microwave irradiation (normal) for 45min. The crude rxn mixture was filtered through a short plug of celiteand the celite plug was washed with EtOAc (˜50 mL). The filtrate waswashed with H₂O (2×30 mL), brine, dried over Na₂SO₄, filtered andconcentrated in vacuo. The resulting residue was purified by silica gelCC (12 g ISCO, gradient 5-75% EtOAc in hexanes) to afford the free baseof the desired product,2-chloro-5-[2-(2,4-difluorophenoxy)-5-nitrophenyl]-4-fluoropyridine as ayellow solid (144 mg, 57%). LCMS (M+H)⁺: 381.

Step 2:5-[2-(2,4-difluorophenoxy)-5-nitrophenyl]-4-fluoro-1-methylpyridin-2-one

A mixture of2-chloro-5-[2-(2,4-difluorophenoxy)-5-nitrophenyl]-4-fluoropyridine (140mg, 0.37 mmol), KOH (62 mg, 1.11 mmol), Pd₂(dba)₃ (17 mg, 5%), and XPhos(18 mg, 10%) was suspended in 1,4-dioxane (1.9 mL) and H₂O (316 μL).After purging the rxn vial with N₂ for 5 min, the capped vial wasstirred at 100° C. for 1 hr. After the mixture cooled to room temp, itwas treated with 1N HCl (aq) (1 mL) and EtOAc (5 mL). The biphasicmixture was filtered through a short plug of celite and the celite plugwas washed with EtOAc (˜50 mL). The filtrate was washed with H₂O (2×30mL), brine, dried over Na₂SO₄, filtered and concentrated in vacuo toafford a orange solid,5-[2-(2,4-difluorophenoxy)-5-nitrophenyl]-4-fluoropyridin-2-ol (LCMS(M+H)⁺363). After the solid was diluted with DMF (2.4 mL), it wastreated with K₂CO₃ (112 mg) and MeI (23 μL). After stirring at room tempfor 5 hr, the mixture was treated with H₂O (10 mL) and extracted withEtOAc (3×10 mL); the combined organic extracts were washed with satdbicarbonate soln (aq), dried over Na₂SO₄, filtered, concentrated invacuo. The resulting residue was purified by silica gel CC (4 g ISCO,gradient 05-95% EtOAc in hexanes) to afford the desired product,5-[2-(2,4-difluorophenoxy)-5-nitrophenyl]-4-fluoro-1-methylpyridin-2-oneas a tan solid (95 mg). LCMS (M+H)⁺: 377.

Step 3:5-[5-amino-2-(2,4-difluorophenoxy)phenyl]-4-fluoro-1-methylpyridin-2-one

A mixture of5-[2-(2,4-difluorophenoxy)-5-nitrophenyl]-4-fluoro-1-methylpyridin-2-one(90 mg, 0.24 mmol), ammonium chloride (26 mg, 0.48 mmol), iron powder(67 mg, 1.2 mmol) suspended in THF (500 μL), H₂O (180 μL), and EtOH (500μL) was heated to 100° C. using microwave irradiation (normal) for 3 hr.The crude rxn mixture was filtered through a short plug of celite andthe celite plug was washed with heated (50° C.) MeOH (˜10 mL). Theresulting filtrate was concentrated in vacuo. The resulting residue wasdiluted with EtOAc (20 ml) and washed with satd bicarbonate soln (aq),dried over anhydrous magnesium sulfate, filtered, and concentrated invacuo to afford the desired product,5-[5-amino-2-(2,4-difluorophenoxy)-phenyl]-4-fluoro-1-methylpyridin-2-one(75 mg, 90%). LCMS (M+H)⁺: 347. The material was carried forward withoutany further purification.

Step 4:N-[4-(2,4-difluorophenoxy)-3-(4-fluoro-1-methyl-6-oxopyridin-3-yl)phenyl]ethanesulfonamide

Ethylsulfonyl chloride (177 mg, 1.4 mmol) was added dropwise to astirred soln of5-[5-amino-2-(2,4-difluorophenoxy)phenyl]-4-fluoro-1-methylpyridin-2-one(72 mg, 0.21 mmol) and pyridine (50 pt, 0.63 mmol) in CH₂Cl₂ (500 μL) at0° C. under N₂. After the mixture was allowed to warm to room temp andstir for 2 hr, it was treated with 1N HCl (3 mL) and extracted withCH₂Cl₂ (3×10 mL); the combined organic extracts were washed with satdbicarbonate soln (aq), dried over Na₂SO₄, filtered and concentrated invacuo. The resulting residue was purified by silica gel CC (4 g ISCO,gradient 0-10% MeOH in CH₂Cl₂) to afford the desired product,N-[4-(2,4-difluorophenoxy)-3-(4-fluoro-1-methyl-6-oxopyridin-3-yl)phenyl]ethanesulfonamide(66 mg, 72%) as a white solid. ¹H NMR (400 MHz, DMSO-d6): δ 1.18-1.26(m, 3H), 3.07-3.16 (m, 2H), 3.45 (s, 3H), 6.22-6.33 (m, 1H), 6.82-6.93(m, 1H), 7.01-7.16 (m, 2H), 7.18-7.28 (m, 2H), 7.38-7.49 (m, 1H),7.95-8.05 (m, 1H), 9.77-9.87 (s, 1H). LCMS (M+H)⁺: 439.

Example 140:N-[3-(5-cyclopropyl-1-methyl-6-oxopyridin-3-yl)-4-(2,4-difluorophenoxy)phenyl]ethanesulfonamide

The title compound was prepared in a manner similar to Example 122,substituting3-cyclopropyl-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-onefor3-fluoro-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one.LCMS (M+H)⁺: 461.

Example 141:N-{4-(2,4-difluorophenoxy)-3-[1-(²H₃)methyl-6-oxopyridin-3-yl]phenyl}ethanesulfonamide

The title compound was prepared in a manner similar to Example 122,substituting1-(²H₃)methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-onefor3-fluoro-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one.LCMS (M+H)⁺: 424.

Example 142:N-[4-(2,4-difluorophenoxy)-3-(2-methyl-1-oxo-5,6,7,8-tetrahydro-2,6-naphthyridin-4-yl)phenyl]ethanesulfonamide

The title compound of Example 127 (240 mg, 0.5 mmol) was hydrogenated(50 psi) at room temp in anhydrous EtOH (30 mL) for 18 hr using PtO₂(0.1 g). Purification by preparative HPLC gave the title compound (40mg, 16.7%) as a white solid. ¹H NMR (Methanol-d4, 400 MHz): δ 7.36 (s.,1H), 7.23 (dd, J₁=8.8 Hz, J₂=2.8 Hz 1H), 7.14 (d, J=2.8 Hz, 1H),7.06-6.96 (m, 2H), 6.91-6.86 (m, 2H), 3.83-3.49 (m, 2H), 3.53 (s, 3H),3.16-2.89 (m, 2H), 3.08 (q, J=7.2 Hz, 2H), 2.55 (t, J=6.0 Hz, 2H), 2.55(t, J=7.2 Hz, 3H). LCMS (M+H)⁺: 476.

Example 143:4-[5-(cyclopropylmethoxy)-2-(methylsulfonylmethyl)pyrimidin-4-yl]-2-methylisoquinolin-1-oneStep 1: 5-(cyclopropylmethoxy)-2-(methylsulfonylmethyl)pyrimidin-4-ol

To the title compound of Example 152, step 1 (5.00 g, 31.6 mmol) in THF(50 mL) at 0° C. was added NaH (1.26 g, 31.6 mmol, 60% in mineral oil).Ethyl formate (2.57 g, 34.76 mmol) was added at 0° C. and the mixturewas heated at 70° C. for 2 h. The mixture was then cooled to room tempand a pre-mixed soln of 2-(methylsulfonyl)-ethanimidamide (6.44 g 47.4mmol) and EtONa (4.3 g, 63.2 mmol) in ethanol (50 mL) was addeddropwise. The mixture was heated at 90° C. for 12 hr, cooled to roomtemp, and solvent was removed under vacuum. H₂O (50 mL) was added to theresidue and the pH was adjusted to 5 with 1M HCl. The resultingprecipitate was collected and washed with H₂O (100 ml), EtOH (50 ml) andMeOH (30 mL) to give the title compound (1.9 g, yield: 23.4%) as a whitesolid. ¹H NMR (DMSO-d6, 400 MHz): δ 11.49 (s, 1H), 6.83 (s, 1H), 6.49(s, 2H), 3.63 (d, J=6.8 Hz, 2H), 3.04 (s, 3H), 1.14-1.10 (m, 1H),0.52-0.49 (m, 2H), 0.27-0.24 (m, 2H). LCMS: 259.0 (M+1)⁺.

Step 2:4-chloro-5-(cyclopropylmethoxy)-2-(methylsulfonylmethyl)pyrimidine

To the title compound of step 1 (1.9 g, 7.36 mmol) in MeCN (30 mL) wasadded Me₄NCl (1.6 g, 14.72 mmol) and POCl₃ (6.8 g, 44.16 mmol). Themixture was heated at 80° C. for 6 hr. After concentration under vacuum,the residue was subjected to EA extractive work-up. Trituration withMeOH (20 mL) gave the title compound (1 g, yield: 49.3%) as a whitesolid. ¹H NMR (CDCl₃, 400 MHz): δ 7.60 (s, 1H), 5.50 (s, 2H), 3.85 (d,J=6.8 H z, 2H), 3.09 (s, 3H), 1.31-1.28 (m, 1H), 0.70-0.65 (m, 2H),0.39-0.36 (m, 2H). LCMS: 277.1 (M+1)⁺.

Step 3:4-[5-(cyclopropylmethoxy)-2-(methylsulfonylmethyl)pyrimidin-4-yl]-2-methylisoquinolin-1-one

The title compound of step 2 (100 mg, 0.36 mmol), the title compound ofExample 89, step 1 (124 mg, 0.43 mmol), Pd(dppf)Cl₂ (27 mg, 0.03 mmol)and K₃PO₄ (154 mg, 0.72 mmol) in dioxane (5 mL) and H₂O (5 drops) wereN₂ purged and heated to 70° C. for 18 hr. After concentration undervacuum, the residue was purified using silica gel chromatographyfollowed by prep-HPLC to give the title compound (61.7 mg, 42.7%) as ayellow solid. ¹H NMR (DMSO-d6, 400 MHz) δ 8.29 (d, J=7.2 Hz, 1H),7.69-7.65 (m, 3H), 7.53 (t, J=7.2 Hz, 1H), 7.44 (d, J=8.0 Hz, 1H), 3.76(d, J=6.8 Hz, 2H), 3.58 (s, 3H), 3.26 (s, 3H), 0.94-0.88 (m, 1H),0.35-0.31 (m, 2H), 0.10-0.08 (m, 2H). LCMS: 400.1 (M+1)⁺.

Example 144:5-[5-(cyclopropylmethoxy)-2-(methylsulfonylmethyl)pyrimidin-4-yl]-1,3-dimethylpyridin-2-one

The title compound of Example 143, step 2 was reacted with1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-onein a manner similar to Example 143, step 3 to give the title compound.¹H NMR (CDCl₃, 400 MHz): δ 8.49 (d, J=2.0 Hz, 1H), 8.18 (s, 1H), 7.60(s, 1H), 3.86 (d, J=6.8 Hz, 2H), 3.67 (s, 3H), 3.11 (s, 3H), 2.24 (s,3H), 1.29-1.27 (m, 1H), 0.72-0.67 (m, 2H), 0.39-0.35 (m, 2H). LCMS:364.1 (M+1)⁺.

Example 145:4-[5-(cyclopropylmethoxy)-2-(methylsulfonylmethyl)pyrimidin-4-yl]-2-methyl-6-(1-methylpyrazol-4-yl)isoquinolin-1-one

The title compound of Example 143, step 2 was reacted with the titlecompound of Example 46, step 2 in a manner similar to Example 143, step3 to give the title compound. ¹H NMR (DMSO-d6, 400 MHz) δ 8.26 (d, J=8.4Hz, 1H), 8.23 (s, 1H), 7.91 (s, 1H), 7.5 (d, J=8.4 Hz, 1H), 7.70 (s,1H), 7.66 (s, 1H), 7.52 (s, 1H), 3.87 (s, 3H), 3.85-3.80 (m, 4H), 3.57(s, 3H), 3.28 (s, 3H), 0.88-0.87 (m, 1H), 0.30-0.25 (m, 2H), 0.07-0.04(m, 2H). LCMS: 480.2 (M+1)⁺.

Example 146:5-[5-(2,4-difluorophenoxy)-2-(methylsulfonylmethyl)pyrimidin-4-yl]-3-methoxy-1-methylpyridin-2-oneStep 1: 5-(2,4-difluorophenoxy)-2-(methylsulfonylmethyl)pyrimidin-4-ol

To a stirred suspension of NaH (960 mg, 24 mmol, 60% in mineral oil) inanhydrous THF (33 mL) was added ethyl formate (1.8 g, 24.3 mmol) and2-(2,4-difluorophenoxy)acetic acid ethyl ester (4.3 g, 19.9 mmol) inanhydrous THF (10 mL). The suspension was stirred at room temp for 0.5hr and then refluxed for 3 hr, cooled, and concentrated under vacuum.The residue was dissolved in EtOH (50 mL) and2-(methylsulfonyl)-ethanimidamide (3.0 g, 22.1 mmol) was added and themixture was refluxed for 18 hr. After concentration under vacuum, H₂O(50 mL) was added and the pH was adjusted to pH 5 with acetic acid.After EA extractive work-up, the residue was dissolved in EA (20 mL) andPE (150 mL) was added. The resulting precipitate (3.0 g, crude) wascollected as a grey solid to give the title compound. LCMS: 317.1(M+1)⁺.

Step 2:4-chloro-5-(2,4-difluorophenoxy)-2-(methylsulfonylmethyl)pyrimidine

To the title compound of step 1 (3.0 g) and N(CH₃)₄Cl (1.6 g, 14.2 mmol)in anhydrous MeCN (30 mL), POCl₃ (8.7 g, 56.9 mmol) was added dropwise.The mixture was stirred at room temp for 0.5 hr and then at 70° C. for 6hr. After concentration under vacuum, H₂O was added and EA extractivework-up was carried out to give the title compound (3.0 g) as a lightyellow solid. LCMS: 335.1 (M+1)⁺.

Step 3:5-[5-(2,4-difluorophenoxy)-2-(methylsulfonylmethyl)pyrimidin-4-yl]-3-methoxy-1-methylpyridin-2-one

The title compound of Example 287, step 1 was treated with4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolanein a manner similar to that outlined for Example 119, step 2 to give3-methoxy-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-onewhich was then reacted with the title compound of step 2 in a mannersimilar to Example 143, step 3 to give the title compound. ¹H NMR(DMSO-d6, 400 MHz) δ 8.37 (s, 1H), 8.36 (d, J=2.0 Hz, 1H), 7.62 (d,J=2.0 Hz, 1H), 7.60-7.54 (m, 1H), 7.51-7.45 (m, 1H), 7.22-7.18 (m, 1H),4.78 (s, 2H), 3.77 (s, 3H), 3.56 (s, 3H), 3.20 (s, 3H). LCMS: 438.1(M+1)⁺.

Example 147:5-[5-(2,4-difluorophenoxy)-2-(methylsulfonylmethyl)pyrimidin-4-yl]-1,3-dimethylpyridin-2-one

The title compound of Example 146, step 2 was reacted with1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-onein a manner similar to Example 143, step 3 to give the title compound.¹H NMR (DMSO-d6, 400 MHz): δ 8.58 (d, J=2.0 Hz, 1H), 8.35 (s, 1H), 8.13(s, 1H), 7.60-7.54 (m, 1H), 7.52-7.46 (m, 1H), 7.22-7.17 (m, 1H), 4.76(s, 2H), 3.56 (s, 3H), 3.18 (s, 3H), 2.08 (s, 3H). LCMS: 422.1 (M+1)⁺.

Example 148:4-[5-(2,4-difluorophenoxy)-2-(methylsulfonylmethyl)pyrimidin-4-yl]-2-methylisoquinolin-1-one

The title compound of Example 146, step 2 was reacted with the titlecompound of Example 89, step 1 in a manner similar to Example 143, step3 to give the title compound. ¹H NMR (DMSO-d6, 400 MHz): δ 8.62 (s, 1H),8.28 (d, J=8.0 Hz, 1H), 7.91 (s, 1H), 7.69-7.68 (m, 2H), 7.58-7.54 (m,1H), 7.45-7.34 (m, 2H), 7.07-7.03 (m, 1H), 4.83 (s, 2H), 3.58 (s, 3H),3.17 (s, 3H). LCMS: 458.1 (M+1)⁺.

Example 149:5-[5-(2,4-difluorophenoxy)-2-methylsulfonylpyrimidin-4-yl]-1,3-dimethylpyridin-2-oneStep 1: 5-(2,4-difluorophenoxy)-2-methylsulfanylpyrimidin-4-ol

To a soln of 2-(2,4-difluorophenoxy)acetic acid ethyl ester (8.0 g,37.01 mmol) and ethyl formate (4.11 g, 55.51 mmol) in dry THF (200 mL)was added NaH (1.55 g, 38.75 mmol) slowly at 0° C. The mixture was thenrefluxed for 2 hr. In a separate flask, sodium ethoxide (3.02 g, 44.41mmol) and S-methylthiopseudourea hemisulfate (6.17 g, 44.41 mmol) inEtOH (100 mL) were stirred at 20° C. for 2 hr and then the resultingmixture was added to the above THF soln. The combined mixture wasrefluxed for 12 hr. After concentration under vacuum, H₂O (20 mL) andHCl (10 mL, aq 1N) were added. The suspended solids were collected andwashed with H₂O (50 mL×3) and EtOH (50 mL×3) and dried to give the titlecompound (6.0 g, 60.0% yield) as a light yellow solid. ¹H NMR (DMSO-d6,400 MHz): δ 7.84 (s, 1H), 7.42-7.34 (m, 1H), 7.04-7.01 (m, 1H), 6.95 (t,J=9.6 Hz, 1H), 2.47 (s, 3H). LCMS: 271.1 (M+1)⁺.

Step 2: 4-chloro-5-(2,4-difluorophenoxy)-2-methylsulfanylpyrimidine

The title compound of step 1 (5.30 g, 19.63 mmol), POCl₃ (18.06 g,117.78 mmol), (Me)₄NCl (3.23 g, 29.47 mmol) in dry CH₃CN (60 mL) wasrefluxed for 12 hr. The mixture was poured into ice-water (50 mL) andsubjected to EA extractive work-up. Concentration under vacuum gaveimpure title compound (4.0 g), which was carried on to the next step.LCMS: 288.99 (M+1)⁺.

Step 3: 4-chloro-5-(2,4-difluorophenoxy)-2-methylsulfonylpyrimidine

To a soln of the title compound of step 2 (4.60 g, 15.93 mmol) in CH₂Cl₂(200 mL) was added mCPBA (13.75 g, 79.68 mmol) slowly at 0° C. Themixture was stirred at 20° C. for 12 hr and then sat. aq Na₂SO₃ (200 mL)was added. EA extractive work-up and silica gel chromatography gave thetitle compound (2.0 g, 39.1% yield) as a yellow solid. ¹H NMR (CDCl₃,400 MHz): δ 8.18 (s, 1H), 7.31-7.27 (m, 1H), 7.10-7.01 (m, 2H), 3.36 (s,3H). LCMS: 320.8 (M+1)⁺.

Step 4:5-[5-(2,4-difluorophenoxy)-2-methylsulfonylpyrimidin-4-yl]-1,3-dimethylpyridin-2-one

A mixture of the title compound from step 3 (100 mg, 0.31 mmol),1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one(93 mg, 0.37 mmol), Pd(dppf)Cl₂ (23 mg, 0.31 mmol) and K₃PO₄ (199 mg,0.94 mmol) in dioxane/H₂O (3 mL/0.5 mL) was N₂ purged and heated at 70°C. for 12 hr. Concentration under vacuum and silica gel chromatography(PE:EA=3:1˜0:1) followed by prep-HPLC gave the title compound (45 mg,35.4%). ¹H NMR (CDCl₃, 400 MHz): δ 8.57 (s, 1H), 8.25 (s, 1H), 8.15 (s,1H), 7.25-7.24 (m, 1H), 7.12-7.07 (m, 1H), 7.03 (t, J=8.0 Hz, 1H), 3.68(s, 3H), 3.38 (s, 3H), 2.25 (s, H). LCMS: 407.9 (M+1)⁺.

Example 150:5-[5-(2,4-difluorophenoxy)-2-methylsulfonylpyrimidin-4-yl]-3-methoxy-1-methylpyridin-2-one

The title compound of Example 149, step 3 was reacted with3-methoxy-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one(see Example 146, step 3) in a manner similar to Example 149, step 4 togive the title compound. ¹H NMR (CDCl₃, 400 MHz): δ 8.35 (d, J=2.0 Hz,1H), 8.18 (s, 1H), 7.70 (d, J=2.0 Hz, 1H), 7.25-7.22 (m, 1H), 7.12-7.08(m, 1H), 7.08-7.04 (m, 1H), 3.93 (s, 3H), 3.70 (s, 3H), 3.38 (s, 3H).LCMS: 423.9 (M+1)⁺.

Example 151:4-[5-(2,4-difluorophenoxy)-2-methylsulfonylpyrimidin-4-yl]-2-methylisoquinolin-1-one

The title compound of Example 149, step 3 was reacted with the titlecompound of Example 89, step 1 in a manner similar to Example 149, step4 to give the title compound. ¹H NMR (CDCl₃, 400 MHz): δ 8.52 (d, J=8.0Hz, 1H), 8.32 (s, 1H), 7.68 (s, 3H), 7.59-7.56 (m, 1H), 7.14-7.08 (m,1H), 7.05-7.00 (m, 1H), 6.96-6.92 (m, 1H), 3.72 (s, 3H), 3.39 (s, 3H).LCMS: 443.9 (M+1)⁺.

Example 152:N-[5-(cyclopropylmethoxy)-4-(2-methyl-1-oxoisoquinolin-4-yl)pyrimidin-2-yl]methanesulfonamideStep 1: ethyl 2-(cyclopropylmethoxy)acetate

Diazoacetic acid ethyl ester (80.00 g, 0.70 mol) was added dropwise tocyclopropanemethanol (60.66 g, 0.84 mol) and [Rh(Ac₂O)₂]₂ (3.1 g, 7.02mmol) in anhydrous CH₂Cl₂ (800 mL) at 0° C. The mixture was stirred at0° C. for 30 min and at room temp for 4 hr. CH₂Cl₂ extractive work-upand silica gel chromatography (PE:EA=100:1˜50:1) gave the title compound(100 g, 90.4% yield) as a colorless oil. ¹H NMR (CDCl₃, 400 MHz): δ4.23-4.19 (m, 2H), 4.09 (s, 2H), 3.38-3.36 (m, 2H), 1.27 (t, J=7.2 Hz,3H), 1.10-1.07 (m, 1H), 0.57-0.52 (m, 2H), 0.24-0.20 (m, 2H).

Step 2: 5-(cyclopropylmethoxy)-2-methylsulfanylpyrimidin-4-ol

To a stirred suspension of NaH (35.20 g, 0.88 mol, 60% in mineral oil)in anhydrous THF (1000 mL) was added ethyl formate (88.80 g, 0.90 mol)and the title compound of step 1 (126.0 g, 0.80 mol) in anhydrous THF(100 mL). The mixture was stirred at room temp for 0.5 hr and refluxedfor 3 hr. In a separate flask, S-methylthiopseudourea hemisulfate(133.44 g, 0.96 mol) and sodium ethoxide (65.28 g, 0.96 mol) in EtOH(200 mL) were stirred at room temp for 1 hr, whereupon this mixture wasadded to the above mixture. There combined mixture was refluxed for 15hr, cooled, and the pH was adjusted to 5 with acetic acid. Afterconcentration under vacuum, silica gel chromatography (DCM:MeOH=50:1 to10:1) gave the title compound (30.00 g, 17.7% yield) as a yellow solid.¹H NMR (CDCl₃, 400 MHz): δ 12.08 (s, 1H), 7.49 (s, 1H), 3.83-3.80 (m,2H), 2.55 (s, 3H), 1.37-1.28 (m, 1H), 0.65-0.62 (m, 2H), 0.37-0.34 (m,2H).

Step 3: 4-chloro-5-(cyclopropylmethoxy)-2-methylsulfanylpyrimidine

To the title compound of step 2 (29.00 g, 136.79 mmol) and N(CH₃)₄Cl(22.47 g, 205.19 mmol) in anhydrous MeCN (300 mL), was added POCl₃(123.93 g, 820.74 mmol). The mixture was stirred at room temp for 30 minand at 70° C. for 1 hr. After concentration under vacuum, EA extractivework-up and silica gel chromatography (PE:EA=50:1˜5:1) gave the titlecompound (20 g, 63.6% yield) as a white solid. ¹H NMR (CDCl₃, 400 MHz):δ 8.16 (s, 1H), 3.95 (d, J=6.8 Hz, 2H), 2.56 (s, 3H), 1.33-1.28 (m, 1H),0.72-0.70 (m, 2H), 0.41-0.37 (m, 2H). LCMS: 230.9 (M+1)⁺.

Step 4: 4-chloro-5-(cyclopropylmethoxy)-2-methylsulfonylpyrimidine

To the title compound of step 3 (19.0 g, 82.60 mmol) in dry CH₂Cl₂ (200mL) at 0° C., m-CPBA (42.62 g, 247.80 mmol) was added over 15 min. Themixture was stirred at 0° C. for 30 min and at room temp overnight. Sat.aq Na₂SO₃ (100 mL) was added and CH₂Cl₂ extractive work-up was carriedout. Trituration with MTBE (300 mL) gave the title compound (17 g, 78.3%yield) as a white solid. ¹H NMR (CDCl₃, 400 MHz): δ 8.37 (s, 1H), 4.13(d, J=6.8 Hz, 2H), 3.33 (s, 3H), 1.39-1.35 (m, 1H), 0.79-0.74 (m, 2H),0.49-0.45 (m, 2H). LCMS: 263.0 (M+1)⁺.

Step 5:4-[5-(cyclopropylmethoxy)-2-methylsulfonylpyrimidin-4-yl]-2-methylisoquinolin-1-one

The title compound of step 4 (5.00 g, 19.08 mmol), the title compound ofExample 89, step 1 (5.98 g, 20.99 mmol), K₃PO₄ (12.13 g, 57.24 mmol),and Pd(dppf)Cl₂ (1.40 g, 1.91 mmol) in dioxane/H₂O (50 mL/5 mL) were N₂purged and heated at 80° C. for 8 hr. Silica gel chromatography(PE:EA=10:1˜1:1) to gave the title compound (5.01 g, yield: 68%) as ayellow solid. ¹H NMR (CDCl₃, 400 MHz): δ 8.53 (s, 2H), 7.67-7.63 (m,2H), 7.57-7.52 (m, 2H), 4.06 (d, J=6.8 Hz, 2H), 3.71 (s, 3H), 3.37 (s,3H), 1.17 (m, 1H), 0.61 (m, 2H), 0.30 (m, 2H). LCMS: 386.1 (M+1)⁺.

Step 6:N-[5-(cyclopropylmethoxy)-4-(2-methyl-1-oxoisoquinolin-4-yl)pyrimidin-2-yl]methanesulfonamide

Sodium hydride (0.93 g, 23.37 mmol, 60% in mineral oil) was added toMeSO₂NH₂ (2.22 g, 23.37 mmol) in dry DMF (30 mL) at 0° C. over 15 min.The mixture was stirred at 0° C. for 1 hr and the title compound of step5 (3.00 g, 7.79 mmol) was added. The mixture was heated at 60° C. for 6hr. After cooling, ice water was added and the pH was adjusted to 5 withacetic acid. The suspended solids were collected and washed with MTBE(50 mL) to afford the title compound (3 g, yield: 96.7%) as an off-whitesolid. ¹H NMR (CDCl₃, 400 MHz): δ 9.80 (s, 1H), 8.53 (d, J=8.0 Hz, 1H),8.42 (s, 1H), 7.97 (d, J=8.4 Hz, 1H), 7.70 (m, 2H), 7.56 (t, J=7.6 Hz,1H), 3.87 (d, J=7.2 Hz, 2H), 3.70 (s, 3H), 3.39 (s, 3H), 1.12 (m, 1H),0.58 (m, 2H), 0.24 (m, 2H). LCMS: 401.1 (M−1)⁺.

Example 153:N-[5-(cyclopropylmethoxy)-4-(1,5-dimethyl-6-oxopyridin-3-yl)pyrimidin-2-yl]methanesulfonamide

The title compound of Example 152, step 4 was reacted with1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-onein a manner similar to Example 152, step 5 and the resulting product wastreated with MeSO₂NH₂ in a manner similar to Example 152, step 6 to givethe title compound. ¹H NMR (DMSO-d6, 400 MHz): δ 10.97 (s, 1H), 8.67 (s,1H), 8.42 (s, 1H), 8.14 (s, 1H), 4.03 (d, J=6.4 Hz, 2H), 3.54 (s, 3H),3.35 (s, 3H), 2.08 (s, 3H), 1.33-1.31 (m, 1H), 0.63-0.61 (m, 2H),0.38-0.37 (m, 2H). LCMS: 365.0 (M+1)⁺.

Example 154:N-[5-(cyclopropylmethoxy)-4-[2-methyl-6-(1-methylpyrazol-4-yl)-1-oxoisoquinolin-4-yl]pyrimidin-2-yl]methanesulfonamide

The title compound of Example 152, step 4 was reacted with the titlecompound of Example 46 step 2 in a manner similar to Example 152, step 5and the resulting product was treated with MeSO₂NH₂ in a manner similarto Example 152, step 6 to give the title compound. ¹H NMR (CDCl₃, 400MHz): δ 11.15 (s, 1H), 8.56 (s, 1H), 8.27 (s, 1H), 8.25 (d, J=7.6 Hz,1H), 7.98 (s, 1H), 7.79 (s, 1H), 7.77 (d, J=9.6 Hz, 1H), 7.70 (s, 1H),3.95 (d, J=7.2 Hz, 2H), 3.85 (s, 3H), 3.57 (s, 3H), 3.32 (s, 3H),1.00-0.99 (m, 1H), 0.37-0.32 (m, 2H), 0.14-0.12 (m, 2H). LCMS: 481.0(M+1)⁺.

Example 155:N-[5-(cyclopropylmethoxy)-4-(2-methyl-1-oxoisoquinolin-4-yl)pyrimidin-2-yl]ethanesulfonamide

The title compound of Example 152, step 5 was treated with EtSO₂NH₂instead of MeSO₂NH₂ in a manner similar to Example 152, step 6 to givethe title compound. ¹H NMR (CDCl₃, 400 MHz) δ 9.00 (s, 1H), 8.53 (d,J=8.0 Hz, 1H), 8.38 (s, 1H), 7.97 (d, J=8.0 Hz, 1H), 7.69 (m, 2H), 7.57(t, J=7.6 Hz, 1H), 3.86 (d, J=6.8 Hz, 2H), 3.70 (s, 3H), 3.63 (q, J=7.2Hz, 2H), 1.43 (t, J=7.2 Hz, 3H), 1.13 (m, 1H), 0.57 (m, 2H), 0.25 (m,2H). LCMS: 415.0 (M+1)⁺.

Example 156:4-[5-(cyclopropylmethoxy)-2-(1,1-dioxo-1,2-thiazolidin-2-yl)pyrimidin-4-yl]-2-methylisoquinolin-1-one

The title compound of Example 152, step 5 was treated with1,1-dioxidoisothiazolidine instead of MeSO₂NH₂ in a manner similar toExample 152, step 6 to give the title compound. ¹H NMR (DMSO-d6, 400MHz): δ 8.56 (s, 1H), 8.30 (d, J=8.0 Hz, 1H), 7.86 (s, 1H), 7.77 (d,J=8.0 Hz, 1H), 7.67 (t, J=7.6 Hz, 1H), 7.55 (t, J=7.6 Hz, 1H), 3.93-3.91(m, 4H), 3.59 (s, 3H), 2.38-2.31 (m, 2H), 1.06-1.01 (m, 1H), 0.44-0.39(m, 2H), 0.20-0.16 (m, 2H). LCMS: 427.1 (M+H)⁺.

Example 157:N-[5-(cyclopropylmethoxy)-4-(6-fluoro-2-methyl-1-oxoisoquinolin-4-yl)pyrimidin-2-yl]ethanesulfonamide

The title compound of Example 47, step 2 was treated with4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolanein a manner similar to Example 89, step 1 and the resulting6-fluoro-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1-onewas coupled to the title compound of Example 152, step 4 in a mannersimilar to Example 152, step 5 and the resulting4-[5-(cyclopropylmethoxy)-2-methylsulfonylpyrimidin-4-yl]-6-fluoro-2-methyl-isoquinolin-1-onewas treated with EtSO₂NH₂ instead of MeSO₂NH₂ in a manner similar toExample 152, step 6 to give the title compound. ¹H NMR (DMSO-d6, 400MHz): δ 11.04 (brs, 1H), 8.54 (s, 1H), 8.36 (dd, J₁=9.2 Hz, J₂=2.4 Hz,1H), 8.01 (s, 1H), 7.65 (dd, J₁=11.2 Hz, J₂=2.4 Hz, 1H), 7.45-7.38 (m,1H), 3.95 (d, J=6.8 Hz, 2H), 3.58 (s, 3H), 3.48 (q, J=7.2 Hz, 2H), 1.22(t, J=7.2 Hz, 3H), 1.16-1.04 (m, 1H), 0.50-0.42 (m, 2H), 0.27-0.20 (m,2H). LCMS: 433.0 (M+1)⁺.

Example 158:N-[5-(cyclopropylmethoxy)-4-(7-fluoro-2-methyl-1-oxoisoquinolin-4-yl)pyrimidin-2-yl]methanesulfonamide

The title compound of Example 58, step 2 was treated with4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolanein a manner similar to Example 89, step 1 and the resulting7-fluoro-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-isoquinolin-1-onewas coupled to the title compound of Example 152, step 4 in a mannersimilar to Example 152, step 5 and the resulting4-[5-(cyclopropylmethoxy)-2-methylsulfonylpyrimidin-4-yl]-7-fluoro-2-methylisoquinolin-1-onewas treated with MeSO₂NH₂ in a manner similar to Example 152, step 6 togive the title compound. ¹H NMR (DMSO-d6, 400 MHz): δ 11.15 (s, 1H),8.55 (s, 1H), 8.36 (dd, J₁=9.2 Hz, J₂=6.0 Hz, 1H), 8.00 (s, 1H), 7.60(dd, J₁=11.2 Hz, J₂=2.4 Hz, 1H), 7.44-7.37 (m, 1H), 3.95 (d, J=7.2 Hz,2H), 3.58 (s, 3H), 3.32 (s, 3H), 1.15-1.03 (m, 1H), 0.49-0.42 (m, 2H),0.26-0.20 (m, 2H). LCMS: 419.0 (M+1)⁺.

Example 159:N-[5-(cyclopropylmethoxy)-4-(6-fluoro-2-methyl-1-oxoisoquinolin-4-yl)pyrimidin-2-yl]methanesulfonamide

The title compound of Example 47, step 2 was treated with4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolanein a manner similar to Example 89, step 1 and the resulting6-fluoro-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1-onewas coupled to the title compound of Example 152, step 4 in a mannersimilar to Example 152, step 5 and the resulting4-[5-(cyclopropylmethoxy)-2-methylsulfonylpyrimidin-4-yl]-6-fluoro-2-methylisoquinolin-1-onewas treated with MeSO₂NH₂ in a manner similar to Example 152, step 6 togive the title compound. ¹H NMR (DMSO-d6, 400 MHz): δ 11.14 (brs, 1H),8.56 (s, 1H), 7.96 (dd, J₁=9.2 Hz, J₂=3.2 Hz, 1H), 7.88 (s, 1H), 7.85(dd, J₁=9.2 Hz, J₂=3.6 Hz, 1H), 7.62-7.55 (m, 1H), 3.94 (d, J=6.8 Hz,2H), 3.60 (s, 3H), 3.32 (s, 3H), 1.11-0.99 (m, 1H), 0.47-0.40 (m, 2H),0.23-0.16 (m, 2H). LCMS: 419.0 (M+1)⁺.

Example 160:N-[5-(cyclopropylmethoxy)-4-(7-fluoro-2-methyl-1-oxoisoquinolin-4-yl)pyrimidin-2-yl]ethanesulfonamide

The title compound of Example 58, step 2 was treated with4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolanein a manner similar to Example 89, step 1 and the resulting7-fluoro-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1-onewas coupled to the title compound of Example 152, step 4 in a mannersimilar to Example 152, step 5 and the resulting4-[5-(cyclopropylmethoxy)-2-methylsulfonylpyrimidin-4-yl]-7-fluoro-2-methylisoquinolin-1-onewas treated with EtSO₂NH₂ instead of MeSO₂NH₂ in a manner similar toExample 152, step 6 to give the title compound. ¹H NMR (CDCl3 400 MHz):δ 8.53 (dd, J₁=8.8 Hz, J₂=6.0 Hz, 1H), 8.40 (s, 1H), 7.77 (s, 1H), 7.69(dd, J=8.8 Hz, 1H), 7.27-7.23 (m, 1H), 3.88 (d, J=6.8 Hz, 2H), 3.69 (s,3H), 3.60 (q, J=7.2 Hz, 2H), 1.43 (t, J=7.2 Hz, 3H), 1.16-1.13 (m, 1H),0.62-0.56 (m, 2H), 0.27-0.26 (m, 2H). LCMS: 433.2 (M+1)⁺.

Example 161:N-[5-(cyclopropylmethoxy)-4-(2-methyl-1-oxoisoquinolin-4-yl)pyrimidin-2-yl]-N-ethylmethanesulfonamide

Ethyl iodide (95 mg, 0.6 mmol) and K₂CO₃ (55 mg, 0.4 mmol) were added toa soln of the title compound of Example 152 (80 mg, 0.2 mmol) in MeCN (5mL). After refluxing 1 hr, the mixture was cooled, concentrated undervacuum and subjected to CH₂Cl₂ extractive work-up. HPLC purificationgave the title compound (13.42 mg, yield: 15.2%) as a yellow solid. ¹HNMR (DMSO-d6, 400 MHz) δ 8.63 (s, 1H), 8.32 (d, J=8.0 Hz, 1H), 7.90 (s,1H), 7.77 (d, J=8.0 Hz, 1H), 7.69 (t, J=7.6 Hz, 1H), 7.56 (t, J=7.6 Hz,1H), 4.02 (q, J=6.8 Hz, 2H), 3.97 (d, J=7.2 Hz, 1H), 3.60 (s, 3H), 3.43(s, 3H), 1.25 (t, J=6.8 Hz, 1H), 1.10-1.07 (m, 1H), 0.46-0.42 (m, 2H),0.24-0.20 (m, 2H). LCMS: 429.1 (M+H)⁺.

Example 162:N-[5-(cyclopropylmethoxy)-4-(1,5-dimethyl-6-oxopyridin-3-yl)pyrimidin-2-yl]-N-ethylmethanesulfonamide

The title compound of Example 153 was treated with ethyl iodide in amanner similar to Example 161 to give the title compound. ¹H NMR (400MHz, DMSO-d₆): δ ppm 0.36-0.42 (m, 2H) 0.60-0.66 (m, 2H) 1.25 (t, J=6.82Hz, 3H) 1.29-1.40 (m, 1H) 2.09 (s, 3H) 3.48 (s, 3H) 3.56 (s, 3H)3.88-4.20 (m, 4H) 8.13 (s, 1H) 8.49 (s, 1H) 8.69 (s, 1H). LCMS: 393(M+H)⁺.

Example 163:N-[5-(cyclopropylmethoxy)-4-(2-methyl-1-oxo-5,6,7,8-tetrahydroisoquinolin-4-yl)pyrimidin-2-yl]methanesulfonamideStep 1: 2-methyl-5,6,7,8-tetrahydroisoquinolin-1-one

The title compound was prepared from the N-methylation of5,6,7,8-tetrahydroisoquinolin-1(2H)-one in a manner similar to Example47, step 1. ¹H NMR (CDCl₃, 400 MHz): δ 7.02 (d, J=7.2 Hz, 1H), 5.90 (d,J=7.2 Hz, 1H), 3.49 (s, 3H), 2.54-2.45 (m, 4H), 1.74-1.69 (m, 4H).

Step 2: 4-bromo-2-methyl-5,6,7,8-tetrahydroisoquinolin-1-one

The title compound was prepared from the bromination of the titlecompound of step 1 in a manner similar to Example 47, step 2. LCMS:241.9 (M+H)⁺.

Step 3:2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6,7,8-tetrahydroisoquinolin-1-one

The title compound of step 2 (3.3 g, 13.7 mmol),4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(6.96 g, 27.4 mmol), Pd₂(dba)₃ (400 mg, 0.43 mmol), X-phos (400 mg, 0.84mmol) and anhydrous KOAc (1.02 g, 41.1 mmol) in anhydrous dioxane (50mL) were heated at 50° C. under N₂ for 12 hr. Silica gel chromatography(PE:EA=5:1) gave the title compound (1.5 g, yield: 38%) as a yellowsolid. ¹H NMR (CDCl₃, 400 MHz): δ 7.62 (s, 1H), 5.28 (s, 3H), 2.82-2.76(m, 2H), 2.55-2.33 (m, 2H), 1.72-1.70 (m, 4H), 1.31 (s, 12H). LCMS:290.0 (M+H)⁺.

Step 4:4-[5-(cyclopropylmethoxy)-2-methylsulfonylpyrimidin-4-yl]-2-methyl-5,6,7,8-tetrahydroisoquinolin-1-one

The title compound of step 3 (200 mg, 0.69 mmol), the title compound ofExample 152, step 4 (218 mg, 0.83 mmol), K₃PO₄ (440 mg, 2.07 mmol) andPd(dppf)Cl₂ (51 mg, 0.7 mmol) in 6:1 dioxane/H₂O (7 mL) were purged withN₂ and heated at 70° C. for 8 hr. After silica gel chromatography(PE:EA=1:1), the title compound (180 mg, yield: 67%) was obtained as alight yellow solid. ¹H NMR (CDCl₃, 400 MHz): δ 8.42 (s, 1H), 7.48 (s,1H), 4.04 (d, J=7.2 Hz, 2H), 3.60 (s, 3H), 3.35 (s, 3H), 2.65-2.62 (m,2H), 2.54-2.50 (m, 2H), 1.80-1.78 (m, 2H), 1.77-1.67 (m, 2H), 1.28-1.25(m, 1H), 0.73-0.71 (m, 2H), 0.41-0.38 (m, 2H).

Step 5:N-[5-(cyclopropylmethoxy)-4-(2-methyl-1-oxo-5,6,7,8-tetrahydroisoquinolin-4-yl)pyrimidin-2-yl]methanesulfonamide

The title compound of step 4 was treated with MeSO₂NH₂ in a mannersimilar to Example 152, step 6 to give the title compound. ¹H NMR(CDCl₃, 400 MHz): δ 8.18 (s, 1H), 7.38 (s, 1H), 3.74 (d, J=6.4 Hz, 2H),3.51 (s, 3H), 3.28 (s, 3H), 2.60-2.53 (m, 2H), 2.50-2.46 (m, 2H),1.74-1.71 (m, 2H), 1.64-1.59 (m, 2H), 1.13-1.10 (m, 1H), 0.60-0.58 (m,2H), 0.25-0.24 (m, 2H). LCMS: 405.1 (M+H)⁺.

Example 164:N-[5-(cyclopropylmethoxy)-4-(2-methyl-1-oxo-5,6,7,8-tetrahydroisoquinolin-4-yl)pyrimidin-2-yl]ethanesulfonamide

The title compound of Example 163, step 4 was treated with treated withEtSO₂NH₂ instead of MeSO₂NH₂ in a manner similar to Example 152, step 6to give the title compound. ¹H NMR (DMSO-d6, 400 MHz): δ 8.32 (s, 1H),7.64 (s, 1H), 3.83 (d, J=6.8 Hz, 2H), 3.44 (s, 3H), 3.30-3.20 (m, 2H),2.47-2.41 (m, 4H), 1.67-1.57 (m, 4H), 1.19-1.13 (m, 4H), 0.51-0.49 (m,2H), 0.24-0.22 (m, 2H). LCMS: 419.1 (M+H)⁺.

Example 165:N-[5-(2,4-difluorophenoxy)-4-(2-methyl-1-oxoisoquinolin-4-yl)pyrimidin-2-yl]methanesulfonamide

The title compound of Example 151 was treated with MeSO₂NH₂ in a mannersimilar to Example 152, step 6 to give the title compound. ¹H NMR(DMSO-d6, 400 MHz) δ 11.50 (s, 1H), 8.59 (s, 1H), 8.25 (s, J=8.0 Hz,1H), 7.87 (s, 1H), 7.77 (d, J=8.0 Hz, 1H), 7.67 (t, J=8.0 Hz, 1H), 7.54(t, J=7.2 Hz, 1H), 7.34-7.28 (m, 1H), 7.20-7.13 (m, 1H), 6.90 (t, J=8.8Hz, 1H), 3.54 (s, 3H), 3.35 (s, 3H). LCMS: 459.0 (M+1)⁺.

Example 166:N-[5-(2,4-difluorophenoxy)-4-(1,5-dimethyl-6-oxopyridin-3-yl)pyrimidin-2-yl]methanesulfonamide

The title compound of Example 149, step 4 was treated with MeSO₂NH₂ in amanner similar to Example 152, step 6 to give the title compound. ¹H NMR(CDCl₃, 400 MHz) δ 8.42 (s, 1H), 8.36 (s, 1H), 8.10-8.12 (m, 2H),6.98-7.05 (m, 2H), 6.87-6.92 (m, 1H), 3.64 (s, 3H), 3.45 (s, 3H), 2.22(s, 3H). LCMS: 423.0 (M+1)⁺.

Example 167:N-[5-(2,4-difluorophenoxy)-4-(5-methoxy-1-methyl-6-oxopyridin-3-yl)pyrimidin-2-yl]methanesulfonamide

The title compound of Example 150 was treated with MeSO₂NH₂ in a mannersimilar to Example 152, step 6 to give the title compound. ¹H NMR(DMSO-d6, 400 MHz): δ 11.37 (s, 1H), 8.34 (s, 1H), 8.26 (s, 1H), 7.58(s, 1H), 7.54-7.50 (m, 1H), 7.28-7.23 (m, 1H), 7.10-7.06 (m, 1H), 3.74(s, 3H), 3.52 (s, 3H), 3.39 (s, 3H). LCMS: 439.0 (M+1)⁺.

Example 168:N-[5-(2,4-difluorophenoxy)-4-(5-methoxy-1-methyl-6-oxopyridin-3-yl)pyrimidin-2-yl]ethanesulfonamide

The title compound of Example 150 was treated with EtSO₂NH₂ instead ofMeSO₂NH₂ in a manner similar to Example 152, step 6 to give the titlecompound. ¹H NMR (CDCl₃, 400 MHz): δ 8.35 (d, J=2.0 Hz, 1H), 8.18 (s,1H), 7.70 (d, J=2.0 Hz, 1H), 7.25-7.22 (m, 1H), 7.12-7.07 (m, 1H),7.04-7.01 (m, 1H), 3.93 (s, 3H), 3.70 (s, 3H), 3.38 (s, 3H). LCMS: 423.9(M+1)⁺.

Example 169:N-[5-(2,4-difluorophenoxy)-4-(1,5-dimethyl-6-oxopyridin-3-yl)pyrimidin-2-yl]ethanesulfonamide

The title compound of Example 149, step 4 was treated with EtSO₂NH₂instead of MeSO₂NH₂ in a manner similar to Example 152, step 6 to givethe title compound. ¹H NMR (DMSO-d6, 400 MHz): δ 9.07 (s, 1H), 8.42 (s,1H), 8.15 (s, 1H), 8.11 (s, 1H), 7.03-6.97 (m, 1H), 6.91-6.87 (m, 1H),3.66-3.61 (m, 5H), 2.22 (s, 3H), 1.44 (t, J=7.6 Hz, 3H). LCMS: 437.0(M+1)⁺.

Example 170:N-[5-(2,4-difluorophenoxy)-4-(2-methyl-1-oxoisoquinolin-4-yl)pyrimidin-2-yl]ethanesulfonamide

The title compound of Example 151 was treated with EtSO₂NH₂ instead ofMeSO₂NH₂ in a manner similar to Example 152, step 6 to give the titlecompound. ¹H NMR (CDCl₃, 400 MHz): δ 9.15 (s, 1H), 8.49 (d, J=7.6 Hz,1H), 8.34 (s, 1H), 8.02 (d, J=8.0 Hz, 1H), 7.71-7.67 (m, 2H), 7.54 (t,J=7.6 Hz, 1H), 6.92-6.86 (m, 2H), 6.79-6.75 (m, 1H), 3.67 (s, 3H), 3.58(q, J=7.6 Hz, 2H), 1.39 (t, J=7.6 Hz, 3H). LCMS: 473.0 (M+1)⁺.

Example 171:4-[5-(2,4-difluorophenoxy)-2-(1,1-dioxo-1,2-thiazolidin-2-yl)pyrimidin-4-yl]-2-methylisoquinolin-1-one

The title compound of Example 151 was treated with1,1-dioxidoisothiazolidine instead of MeSO₂NH₂ in a manner similar toExample 152, step 6 to give the title compound. ¹H NMR (DMSO-d6, 400MHz): δ 8.63 (s, 1H), 8.24 (d, J=8.0 Hz, 1H), 7.86 (s, 1H), 7.83 (d,J=8.0 Hz, 1H), 7.65 (t, J=7.2 Hz, 1H), 7.53 (t, J=7.2 Hz, 1H), 7.31-7.26(m, 1H), 7.13-7.07 (m, 1H), 6.89-6.87 (m, 1H), 3.97 (t, J=6.4 Hz, 2H),3.57 (t, J=7.2 Hz, 2H), 3.54 (s, 3H), 2.40-2.33 (m, 2H). LCMS: 485.2(M+H)⁺.

Example 172:N-[5-(2,4-difluorophenoxy)-4-(2-methyl-1-oxo-5,6,7,8-tetrahydroisoquinolin-4-yl)pyrimidin-2-yl]methanesulfonamide

The title compound of Example 149, step 3 was reacted with the titlecompound of Example 163, step 3 in a manner similar to Example 163, step4 and the resulting product was treated with MeSO₂NH₂ in a mannersimilar to Example 163, step 5 to give the title compound. ¹H NMR(DMSO-d6, 400 MHz): δ 8.16 (s, 1H), 7.46 (s, 1H), 7.25-7.20 (m, 1H),6.90-6.84 (m, 2H), 3.34 (s, 3H), 2.80 (s, 3H), 2.41-2.29 (m, 4H),1.60-1.48 (m, 4H). LCMS: 463.1 (M+H)⁺.

Example 173:N-[5-(2,4-difluorophenoxy)-4-(2-methyl-1-oxo-5,6,7,8-tetrahydroisoquinolin-4-yl)pyrimidin-2-yl]ethanesulfonamide

The title compound of Example 149, step 3 was reacted with the titlecompound of Example 163, step 3, in a manner similar to Example 163,step 4, and the resulting4-[5-(2,4-difluorophenoxy)-2-methylsulfonylpyrimidin-4-yl]-2-methyl-5,6,7,8-tetrahydroisoquinolin-1-onewas treated with EtSO₂NH₂ instead of MeSO₂NH₂ in a manner similar toExample 163, step 5, to give the title compound. ¹H NMR (DMSO-d6, 400MHz): δ 8.38 (s, 1H), 7.61 (s, 1H), 7.35-7.31 (m, 1H), 7.04-6.95 (m,2H), 3.41 (s, 3H), 3.30-3.20 (m, 2H), 2.42-2.40 (m, 2H), 2.32-2.30 (m,2H), 1.61-1.51 (m, 4H), 1.18 (t, J=7.2 Hz, 3H). LCMS: 477.1 (M+H)⁺.

Example 174:4-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-6-fluoro-2-methylisoquinolin-1-one

A mixture of 4-bromo-6-fluoro-2-methylisoquinolin-1-one (500.00 mg, 1.95mmol),2-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(1.07 g, 2.92 mmol), K₃PO₄ (1.24 g, 5.85 mmol) and Pd(dppf)Cl₂ (0.1 g,cat.) in dioxane/H₂O (30 mL/4 mL) was stirred at 70° C. for 12 hr underAr. The mixture was concentrated and the residue purified by CC(PE:EA=1:1) to give a pink solid. The pink solid was further purified byCC (DCM:EA=4:1) to afford the title compound (0.13 g, 16%) as a lightyellow solid. ¹H NMR (CDCl₃, 400 MHz): δ 8.54 (brs, 1H), 7.96 (dd,J₁=8.8 Hz, J₂=2.4 Hz, 1H), 7.81 (d, J=2.0 Hz, 1H), 7.22-7.20 (m, 1H),7.15-7.13 (m, 1H), 7.1 (d, J=8.8 Hz, 1H), 6.78 (dd, J₁=10.4 Hz, J₂=2.4Hz, 1H), 3.90 (t, J=7.6 Hz, 2H), 3.68 (s, 3H), 3.15 (q, J=7.6 Hz, 2H),1.33 (t, J=7.6 Hz, 3H), 1.06-1.02 (m, 1H), 0.50-0.43 (m, 2H), 0.15-0.14(m, 2H). LCMS (M+H)⁺: 416.0.

Example 175:2-methyl-4-[5-methylsulfonyl-2-(oxolan-3-yloxy)phenyl]isoquinolin-1-oneStep 1: 4-(2-fluoro-5-methylsulfonylphenyl)-2-methylisoquinolin-1-one

A mixture of compound2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1-one (4.1 g, 14.5 mmol),2-bromo-4-methylsulfonyl-1-fluorobenzene (3.5 g, 13.8 mmol) prepared ina similar manner to Example 79 steps 1-2, CsF (6.3 g, 41.3 mmol), andPd(dppf)Cl₂ (1.0 g, 1.38 mmol) in DME (70 mL) and MeOH (35 ml) wasstirred at 70° C. for 12 hr under N₂. The mixture was concentrated andthe residue was purified by CC (PE:EA=2:1˜0:1) to give the titlecompound (3.4 g, 74.4%) as a red solid. LCMS (M+H)⁺: 331.9 (M+1)⁺.

Step 2:2-methyl-4-[5-methylsulfonyl-2-(oxolan-3-yloxy)phenyl]isoquinolin-1-one

To a soln of oxolan-3-ol (175.0 mg, 1.99 mmol) in anhydrous DMF (3 mL)was added NaH (66.0 mg, 1.65 mmol, 60% in mineral oil) at 0° C. and thenstirred at 0° C. for 0.5 hr.4-(2-fluoro-5-methylsulfonylphenyl)-2-methylisoquinolin-1-one (110.0 mg,0.33 mmol) was added. The mixture was stirred at 0° C. for 0.5 hr andthen at room temp for 3 hr. It was then quenched with aq sat′d NH₄Cl (20mL) and extracted with EA (20 mL×3). The combined organic layers werewashed with brine (40 mL), dried over Na₂SO₄, and concentrated underreduced pressure to afford a crude product which was purified byprep-HPLC to give the title compound (62.0 mg, 39.7%) as a light yellowsolid. ¹H NMR (CDCl₃, 400 MHz): δ 8.51 (d, J=7.6 Hz, 1H), 8.00 (dd,J₁=8.8 Hz, J₂=2.4 Hz, 1H), 7.89 (d, J=2.4 Hz, 1H), 7.58-7.51 (m, 2H),7.11-7.03 (m, 3H), 5.01-4.98 (m, 1H), 3.97 (dd, J₁=10.4 Hz, J₂=4.8 Hz,1H), 3.76-3.70 (m, 2H), 3.67 (s, 3H), 3.61-3.42 (m, 1H), 3.11 (s, 3H),2.18-1.88 (m, 2H). LCMS (M+H)⁺: 400.0 (M+1)⁺.

Example 176:2-methyl-4-[5-methylsulfonyl-2-(oxan-4-yloxy)phenyl]isoquinolin-1-one

The title compound was prepared in a manner similar to Example 175, bysubstituting oxan-4-ol for oxolan-3-ol in step 2. ¹H NMR (CDCl₃, 400MHz): δ 8.52 (d, J=7.6 Hz, 1H), 8.00 (dd, J₁=8.8 Hz, J₂=2.4 Hz, 1H),7.89 (d, J=2.4 Hz, 1H), 7.63-7.50 (m, 2H), 7.19 (d, J=7.6 Hz, 1H), 7.11(d, J=8.8 Hz, 1H), 7.09 (s, 1H), 4.65-4.61 (m, 1H), 3.71 (s, 3H),3.53-3.45 (m, 4H), 3.11 (s, 3H), 1.92-1.88 (m, 2H), 1.62-1.54 (m, 2H).LCMS (M+H)⁺: 414.1 (M+1)⁺.

Example 177:4-(2-ethoxy-5-methylsulfonylphenyl)-2-methylisoquinolin-1-one

The title compound was prepared in a manner similar to Example 175, bysubstituting ethanol for oxolan-3-ol in step 2. ¹H NMR (CDCl₃, 400 MHz):δ 8.52 (d, J=8.0 Hz, 1H), 8.01 (dd, J₁=8.8 Hz, J₂=2.4 Hz, 1H), 7.86 (d,J=2.4 Hz, 1H), 7.57 (t, J=7.2 Hz, 1H), 7.52 (t, J=7.2 Hz, 1H), 7.13 (t,J=7.2 Hz, 2H), 7.08 (s, 1H), 4.12-4.09 (m, 2H), 3.68 (s, 3H), 3.10 (s,3H), 1.18 (t, J=7.2 Hz, 1H). LCMS (M+H)⁺: 358.0 (M+1)⁺.

Example 178:2-methyl-4-(5-methylsulfonyl-2-propoxyphenyl)isoquinolin-1-one

The title compound was prepared in a manner similar to Example 175, bysubstituting propan-1-ol for oxolan-3-ol in step 2. ¹H NMR (CDCl₃, 400MHz): δ 8.51 (d, J=8.0 Hz, 1H), 8.00 (dd, J₁=8.8 Hz, J₂=2.4 Hz, 1H),7.86 (d, J=2.4 Hz, 1H), 7.56 (t, J=7.2 Hz, 1H), 7.50 (t, J=7.2 Hz, 1H),7.14 (d, J=7.2 Hz, 1H), 7.12 (d, J=8.8 Hz, 1H), 7.07 (s, 1H), 4.00-3.94(m, 2H), 3.67 (s, 3H), 3.10 (s, 3H), 1.60-1.52 (m, 2H), 0.68 (t, J=7.2Hz, 1H). LCMS (M+H)⁺: 372.0 (M+1)⁺.

Example 179:2-methyl-4-[5-methylsulfonyl-2-(oxan-3-yloxy)phenyl]isoquinolin-1-one

The title compound was prepared in a manner similar to Example 175, bysubstituting oxan-3-ol for oxolan-3-ol in step 2. ¹H NMR (CDCl₃, 400MHz): δ 8.51 (d, J=8.0 Hz, 1H), 7.98 (dd, J₁=8.8 Hz, J₂=2.4 Hz, 1H),7.88 (d, J=2.4 Hz, 1H), 7.56 (t, J=7.2 Hz, 1H), 7.52 (t, J=7.2 Hz, 1H),7.18 (d, J=8.0 Hz, 1H), 7.12-7.06 (m, 2H), 4.43-4.41 (m, 1H), 3.79-3.78(m, 1H), 3.67 (s, 3H), 3.66-3.63 (m, 1H), 3.39-3.34 (m, 2H), 3.10 (s,3H), 2.02-1.93 (m, 2H), 1.59-1.48 (m, 2H). LCMS (M+H)⁺: 414.1 (M+1)⁺.

Example 180:4-[2-(trans-4-hydroxycyclohexyl)oxy-5-methylsulfonylphenyl]-2-methylisoquinolin-1-oneStep 1:4-[2-[4-[tert-butyl(dimethyl)silyl]oxycyclohexyl]oxy-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one

The title compound was prepared in a manner similar to Example 175, bysubstituting trans-4-[tert-butyl(dimethyl)silyl]oxycyclohexan-1-ol foroxolan-3-ol in step 2. LCMS (M+H)⁺542.2 (M+1)⁺.

Step 2:4-[2-(trans-4-hydroxycyclohexyl)oxy-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one

To a soln of the title compound from step 1 (180.0 mg, 0.33 mmol) in dryMeOH (5 mL) and DCM (3 mL) was added dropwise HCl/MeOH (0.3 mL, 1.2mmol, 4M) at 0° C. and then stirred at room temp for 20 min. TLC showedthe starting material was consumed completely. The mixture wasconcentrated and the residue was purified by prep-HPLC to afford thetitle compound (130.0 mg, 97.8%) as a white solid. ¹H NMR (CDCl₃, 400MHz): δ 8.50 (d, J=7.6 Hz, 1H), 7.98 (dd, J₁=8.8 Hz, J₂=2.8 Hz, 1H),7.86 (d, J=2.4 Hz, 1H), 7.55 (t, J=6.8 Hz, 1H), 7.51 (t, J=6.8 Hz, 1H),7.16 (d, J=7.6 Hz, 1H), 7.11 (d, J=8.8 Hz, 1H), 7.05 (s, 1H), 4.42-4.35(m, 1H), 3.67 (s, 3H), 3.65-3.62 (m, 1H), 3.10 (s, 3H), 2.01-1.89 (m,2H), 1.71-1.65 (m, 2H), 1.36-1.34 (m, 4H). LCMS (M+H)⁺: 428.1 (M+1)⁺.

Example 181:4-[5-ethylsulfonyl-2-(trans-4-hydroxycyclohexyl)oxyphenyl]-2-methylisoquinolin-1-oneStep 1:4-[2-[4-[tert-butyl(dimethyl)silyl]oxycyclohexyl]oxy-5-ethylsulfonylphenyl]-2-methylisoquinolin-1-one

The title compound was prepared in a manner similar to Example 175 bysubstituting 2-bromo-4-ethylsulfonyl-1-fluorobenzene for2-bromo-4-methylsulfonyl-1-fluorobenzene in step 1. LCMS (M+H)⁺: 345.9(M+1)⁺.

Step 2:4-[5-ethylsulfonyl-2-(trans-4-hydroxycyclohexyl)oxyphenyl]-2-methylisoquinolin-1-one

To a soln of trans-1,4-cyclohexanediol (504.0 mg, 4.34 mmol) inanhydrous DMF (4 mL) was added NaH (139.0 mg, 3.47 mmol, 60% in mineraloil) at 0° C. and then stirred at 0° C. for 1 hr. The compound from step1 (100.0 mg, 0.29 mmol) was added. The mixture was stirred at 0° C. for0.5 hr and then at room temp 18 hr. It was then quenched with MeOH (4mL) and filtered. The filtrate was purified by prep-HPLC to give thetitle compound (37.0 mg, 30.0%) as an off-white solid. ¹H NMR (CDCl₃, 40MHz): δ 8.51 (d, J=7.6 Hz, 1H), 7.94 (dd, J₁=8.8 Hz, J₂=2.4 Hz, 1H),7.83 (d, J=2.0 Hz, 1H), 7.56 (t, J=6.8 Hz, 1H), 7.51 (t, J=6.8 Hz, 1H),7.16 (d, J=7.6 Hz, 1H), 7.11 (d, J=8.8 Hz, 1H), 7.05 (s, 1H), 4.43-4.18(m, 1H), 3.67 (s, 3H), 3.65-3.62 (m, 1H), 3.16 (q, J=7.6 Hz, 2H),2.00-1.90 (m, 2H), 1.71-1.65 (m, 2H), 1.42-1.30 (m, 7H). LCMS (M+H)⁺:442.0 (M+1)⁺.

Example 182:4-[2-(trans-4-aminocyclohexyl)oxy-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one

A mixture of4-(2-fluoro-5-methylsulfonylphenyl)-2-methylisoquinolin-1-one (200 mg,0.60 mmol), trans-4-aminocyclohexan-1-ol (278 mg, 2.42 mmol) and Cs₂CO₃(591 mg, 1.81 mmol) in DMSO (4 mL) was stirred at 120° C. for 12 hr. H₂O(20 mL) was added and the mixture was extracted with EtOAc (3×20 mL).The combined organic layers were washed with brine (20 mL), dried overNa₂SO₄ and concentrated. The residue was purified by prep-HPLC to givethe title compound (103.15 mg, 36.9%) as its hydrochloride salt. ¹H NMR(DMSO-d6, 400 MHz): δ 8.28 (d, J=8.0 Hz, 1H), 8.10 (s, 3H), 7.95 (dd,J₁=8.8 Hz, J₂=2.4 Hz, 1H), 7.80 (d, J=2.4 Hz, 1H), 7.63 (t, J=7.2 Hz,1H), 7.51-7.49 (m, 3H), 7.14 (d, J=8.0 Hz, 1H), 4.50-4.44 (m, 1H), 3.56(s, 3H), 3.22 (s, 3H), 2.95-2.85 (m, 1H), 2.00-1.94 (m, 2H), 1.84 (d,J=11.2 Hz, 2H), 1.47-1.41 (m, 2H), 1.20-1.12 (m, 2H). LCMS (M+H)⁺: 427.1(M+H)⁺.

Example 183:4-[2-(cis-4-aminocyclohexyl)oxy-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one

To compound cis-4-aminocyclohexan-1-ol (275 mg, 1.81 mmol) in DMF (3mL), was added NaH (127 mg, 3.17 mmol, 60% in mineral oil) in oneportion at 0° C. The mixture was stirred at 0° C. for 30 min,4-(2-fluoro-5-methylsulfonylphenyl)-2-methylisoquinolin-1-one (150.00mg, 0.45 mmol) was added in one portion and the mixture stirred at 0° C.for 2 hr. The rxn was diluted with H₂O (20 mL) and extracted with EA(3×20 mL). The combined organic layers were washed with satd brine (2×20mL), dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum.The residue was purified by prep-HPLC to give the title compound as itshydrochloride salt (91.01 mg, 47.1%). ¹H NMR (DMSO-d6, 400 MHz): δ 8.29(d, J=8.0 Hz, 1H), 8.00 (s, 3H), 7.95 (dd, J₁=8.8 Hz, J₂=2.0 Hz, 1H),7.81 (d, J=2.0 Hz, 1H), 7.64 (t, J=7.2 Hz, 1H), 7.56 (s, 1H), 7.51 (t,J=7.2 Hz, 1H), 7.40 (d, J=8.8 Hz, 1H), 7.40 (d, J=8.0 Hz, 1H), 4.70 (s,1H), 3.59 (s, 3H), 3.22 (s, 3H), 2.96-2.94 (m, 1H), 1.85-1.82 (m, 1H),1.64-1.46 (m, 5H), 1.32-1.26 (m, 1H), 1.04-0.98 (m, 1H). LCMS (M+H)⁺:427.0 (M+H)⁺.

Example 184:4-(2-but-2-ynoxy-5-methylsulfonylphenyl)-2-methylisoquinolin-1-one

The title compound was prepared in a manner similar to Example 175, bysubstituting but-2-yn-1-ol for oxolan-3-ol in step 2. ¹H NMR (CDCl₃, 400MHz): δ 8.52 (d, J=7.6 Hz, 1H), 8.03 (d, J=8.8 Hz, 1H), 7.87 (s, 1H),7.59-7.50 (m, 2H), 7.32 (d, J=8.8 Hz, 1H), 7.15 (d, J=8.4 Hz, 1H), 7.64(t, J=8.0 Hz, 1H), 7.08 (s, 1H), 4.68 (s, 2H), 3.67 (s, H), 3.11 (s,1H), 1.85 (s, 1H). LCMS (M+H)⁺: 382.1 (M+H)⁺.

Example 185:4-(2-but-2-ynoxy-5-ethylsulfonylphenyl)-2-methylisoquinolin-1-one

The title compound was prepared in a manner similar to Example 181, bysubstituting but-2-yn-1-ol for trans-1,4-cyclohexanediol in step 2. ¹HNMR (CDCl₃, 400 MHz) δ: 8.51 (d, J=7.6 Hz, 1H), 8.00 (dd, J₁=8.8 Hz,J₂=2.0 Hz, 1H), 7.83 (s, 1H), 7.61 (d, J=7.6 Hz, 1H), 7.55 (d, J=7.6 Hz,1H), 7.33 (d, J=8.8 Hz, 1H), 7.18 (d, J=8.0 Hz, 1H), 7.12 (s, 1H), 4.68(s, 2H), 3.72 (s, 3H), 3.17 (q, J=7.2 Hz, 2H), 1.85 (s, 3H), 1.34 (t,J=7.2 Hz, 3H). LCMS (M+H)⁺: 396.0 (M+H)⁺.

Example 186:6-fluoro-4-[2-(trans-4-hydroxycyclohexyl)oxy-5-methylsulfonylphenyl]-2-methylisoquinolin-1-oneStep 1:6-fluoro-4-(2-fluoro-5-methylsulfonylphenyl)-2-methylisoquinolin-1-one

The title compound was prepared in a manner similar to Example 174, bysubstituting2-(2-fluoro-5-methylsulfonylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolanefor2-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.LCMS (M+H)⁺: 349.9 (M+H)⁺.

Step 2:4-[2-[4-[tert-butyl(dimethyl)silyl]oxycyclohexyl]oxy-5-methylsulfonylphenyl]-6-fluoro-2-methylisoquinolin-1-one

The title compound was prepared in a manner similar to Example 180 step1, by substituting6-fluoro-4-(2-fluoro-5-methylsulfonylphenyl)-2-methylisoquinolin-1-onefor 4-(2-fluoro-5-methylsulfonylphenyl)-2-methylisoquinolin-1-one. Thecrude product was used directly in the next step without furtherpurification. LCMS (M+H)⁺: 560.3 (M+H)⁺.

Step 3:6-fluoro-4-[2-(trans-4-hydroxycyclohexyl)oxy-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one

The tert-butyl(dimethyl)silyl ether was deprotected in a manner similarto Example 180 step 2. ¹H NMR (CDCl₃, 400 MHz): δ 8.53-8.49 (m, 1H),7.99 (dd, J₁=8.8 Hz, J₂=2.4 Hz, 1H), 7.85 (d, J=2.0 Hz, 1H), 7.21-7.18(m, 1H), 7.12 (d, J=8.8 Hz, 1H), 7.08 (s, 1H), 6.78 (dd, J₁=10.0 Hz,J₂=2.4 Hz, 1H), 4.46-4.44 (m, 1H), 3.66-3.65 (m, 4H), 3.10 (s, 3H),2.02-1.99 (m, 2H), 1.73-1.71 (m, 2H), 1.43-1.37 (m, 4H). LCMS (M+H)⁺:446.0 (M+H)⁺.

Example 187:7-fluoro-4-[2-(trans-4-hydroxycyclohexyl)oxy-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one

The title compound was prepared in a manner similar to Example 186, bysubstituting 4-bromo-7-fluoro-2-methylisoquinolin-1-one for4-bromo-6-fluoro-2-methylisoquinolin-1-one in step 1. ¹H NMR (CDCl₃, 400MHz): δ 8.16-8.14 (m, 1H), 7.99 (dd, J₁=8.8 Hz, J₂=2.4 Hz, 1H), 7.86 (d,J=2.4 Hz, 1H), 7.28-7.27 (m, 1H), 7.18-7.12 (m, 2H), 7.01 (s, 1H),4.43-4.42 (m, 1H), 3.67-3.66 (m, 4H), 3.10 (s, 3H), 1.98-1.97 (m, 2H),1.72-1.71 (m, 2H), 1.39-1.32 (m, 4H). LCMS (M+H)⁺: 446.0 (M+H)⁺.

Example 188:4-[5-ethylsulfonyl-2-(trans-4-hydroxycyclohexyl)oxyphenyl]-6-fluoro-2-methylisoquinolin-1-one

The title compound was prepared in a manner similar to Example 186, bysubstituting2-(5-ethylsulfonyl-2-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolanefor2-(2-fluoro-5-methylsulfonylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolanein step 1. ¹H NMR (CDCl₃, 400 MHz): δ 8.53-8.50 (m, 1H), 7.97-7.94 (m,1H), 7.82 (d, J=2.4 Hz, 1H), 7.22-7.18 (m, 1H), 7.13 (d, J=8.8 Hz, 1H),7.08 (s, 1H), 6.79-6.76 (m, 1H), 4.46-4.44 (m, 1H), 3.70-3.64 (m, 4H),3.16 (q, J=7.6 Hz, 2H), 2.00-1.88 (m, 3H), 1.72-1.71 (m, 2H), 1.40-1.30(m, 7H). LCMS (M+H)⁺: 460.1 (M+H)⁺.

Example 189:4-[5-ethylsulfonyl-2-(trans-4-hydroxycyclohexyl)oxyphenyl]-7-fluoro-2-methylisoquinolin-1-oneStep 1:4-(5-ethylsulfonyl-2-fluorophenyl)-7-fluoro-2-methylisoquinolin-1-one

A mixture of 4-bromo-7-fluoro-2-methylisoquinolin-1-one (100 mg, 0.39mmol),2-(5-ethylsulfonyl-2-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(148 mg, 0.47 mmol), Pd(dppf)Cl₂ (29 mg, 0.04 mmol) and K₃PO₄ (207 mg,0.98 mmol) in dioxane (6 mL) and H₂O (1 mL) was heated to 70° C. for 18hr under N₂. The mixture was concentrated and the residue was purifiedby CC on silica gel (PE:EA=1:1) to give compound 12 (70 mg, yield: 49%)as a yellow solid. LCMS (M+H)⁺: 364.1 (M+H)⁺.

Step 2:4-[2-[4-[tert-butyl(dimethyl)silyl]oxycyclohexyl]oxy-5-ethylsulfonylphenyl]-7-fluoro-2-methylisoquinolin-1-one

To a soln of trans-4-[tert-butyl(dimethyl)silyl]oxycyclohexan-1-ol (87mg, 0.38 mmol) in dry DMF (2 mL) was added NaH (15 mg, 0.38 mmol, 60% inmineral oil) in portions under N₂ at 0° C. and the mixture was stirredat 20° C. for 1 hr. Then the title compound from step 1 (70 mg, 0.19mmol) was added and the mixture was stirred at 20° C. for 4 hr. Themixture was quenched with H₂O (5 mL) and extracted with EtOAc (3×5 mL).The combined organic layers were dried over Na₂SO₄ and concentrated togive the title compound as a yellow gum (65 mg) which was used directlyin the next step without further purification. LCMS (M+H)⁺: 574.3(M+H)⁺.

Step 3:4-[5-ethylsulfonyl-2-(trans-4-hydroxycyclohexyl)oxyphenyl]-7-fluoro-2-methylisoquinolin-1-one

The tert-butyl(dimethyl)silyl ether was deprotected in a manner similarto Example 180 step 2. ¹H NMR (CDCl₃, 400 MHz): δ 8.16 (dd, J₁=9.2 Hz,J₂=2.4 Hz, 1H), δ 7.96 (dd, J₁=8.4 Hz, J₂=2.4 Hz, 1H), 7.82 (d, J=2.4Hz, 1H), 7.32-7.29 (m, 1H), 7.18-7.11 (m, 2H), 7.01 (s, 1H), 4.42-4.42(m, 1H), 3.67 (s, 3H), 3.18 (q, J=7.6 Hz, 2H), 1.97-1.88 (m, 3H),1.72-1.71 (m, 2H), 1.40-1.32 (m, 7H). LCMS (M+H)⁺: 460.1 (M+H)⁺.

Example 190:2-methyl-4-[5-methylsulfonyl-2-(oxolan-3-ylamino)phenyl]isoquinolin-1-oneStep 1: N-(2-bromo-4-methylsulfonylphenyl)oxolan-3-amine

A mixture of 2-bromo-1-fluoro-4-methylsulfonylbenzene (0.8 g, 3.16mmol), oxolan-3-amine (1.38 g, 15.8 mmol) and K₂CO₃ (0.87 g, 6.32 mmol)in DMSO (15 mL) was stirred at 100° C. for 5 hr. It was cooled to roomtemp and H₂O (50 mL) was added. The mixture was extracted with EtOAc (50mL×3) and the combined organic layers were washed with brine (50 mL),dried over Na₂SO₄, filtered and concentrated. The residue was purifiedby CC (PE:EA=50:1˜3:1) to give the title compound (0.7 g, yield:69.16%). ¹H NMR (CDCl₃, 400 MHz): δ 8.00 (d, J=1.2 Hz, 1H), 7.74 (d,J=8.8 Hz, 1H), 6.67 (d, J=8.8 Hz, 1H), 5.03 (d, J=6.4 Hz, 1H), 4.23-4.13(m, 1H), 4.07-3.98 (m, 2H), 3.96-3.87 (m, 1H), 3.83-3.76 (m, 1H), 3.03(s, 3H), 2.43-2.32 (m, 1H), 1.98-1.88 (m, 1H). LCMS (M+H)⁺: 320.0;(M+H)⁺: 322.0.

Step 2:2-methyl-4-[5-methylsulfonyl-2-(oxolan-3-ylamino)phenyl]isoquinolin-1-one

A mixture of2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1-one(100 mg, 0.35 mmol), the compound from Step 1 (102 mg, 0.32 mmol), K₃PO₄(186 mg, 0.88 mmol) and Pd(dppf)Cl₂ (29 mg, 0.04 mmol) in dioxane (5 mL)and H₂O (1 mL) was purged three times with N₂ and then stirred at 70° C.for 18 hr under N₂. The mixture was filtered and concentrated. Theresidue was purified by prep-HPLC to give the title compound (56.02 mg,yield: 40.1%) as a light yellow solid. ¹H NMR (CDCl₃, 400 MHz): δ 8.54(d, J=8.0 Hz, 1H), 7.89 (dd, J₁=8.4 Hz, J₂=2.4 Hz, 1H), 7.69 (s, 1H),7.64-7.52 (m, 2H), 7.13 (s, 1H), 7.13-7.08 (m, 1H), 6.78 (dd, J₁=8.8 Hz,J₂=5.6 Hz, 1H), 4.17 (s, 2H), 3.94-3.86 (m, 1H), 3.79-3.72 (m, 1H),3.72-3.64 (m, 1H), 3.67 (s, 3H), 3.58-3.49 (m, 1H), 3.07 (s, 3H),2.32-2.18 (m, 1H), 1.76-1.63 (m, 1H). LCMS (M+H)⁺: 399.1 (M+H)⁺.

Example 191:2-methyl-4-[5-methylsulfonyl-2-(oxan-4-ylamino)phenyl]isoquinolin-1-oneStep 1: N-(2-bromo-4-methylsulfonylphenyl)oxan-4-amine

The title compound was prepared in a manner similar to Example 190 step1, by substituting oxan-3-amine for oxolan-3-amine. ¹H NMR (CDCl₃, 400MHz): δ 7.98 (d, J=1.8 Hz, 1H), 7.70 (dd, J₁=8.8 Hz, J₂=1.8 Hz, 1H),6.70 (d, J=8.8 Hz, 1H), 4.85 (d, J=7.2 Hz, 1H), 4.08-3.99 (m, 2H),3.69-3.60 (m, 1H), 3.60-3.52 (m, 2H), 3.03 (s, 3H), 2.10-2.02 (m, 2H),1.68-1.55 (m, 2H). LCMS (M+H)⁺: 334.0; (M+H)⁺: 336.0.

Step 2:2-methyl-4-[5-methylsulfonyl-2-(oxan-4-ylamino)phenyl]isoquinolin-1-one

The title compound was prepared in a manner similar to Example 190 step2, by substituting N-(2-bromo-4-methylsulfonylphenyl)oxan-4-amine forN-(2-bromo-4-methyl-sulfonylphenyl)oxolan-3-amine. ¹H NMR (CDCl₃, 400MHz) δ 8.52 (d, J=7.6 Hz, 1H), 7.85 (dd, J₁=8.8 Hz, J₂=2.0 Hz, 1H), 7.67(d, J=2.0 Hz, H), 7.63-7.52 (m, 2H), 7.16-7.11 (m, 2H), 6.81 (d, J=8.8Hz, 1H), 4.00 (d, J=7.6 Hz, 1H), 3.93-3.82 (m, 2H), 3.64 (s, 3H),3.63-3.54 (m, 1H), 3.51-3.42 (m, 2H), 3.06 (s, 3H), 1.95-1.87 (m, 2H),1.37-1.24 (m, 1H). LCMS (M+H)⁺: 413.0 (M+H)⁺.

Example 192:4-[2-[(trans-4-hydroxycyclohexyl)amino]-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one

A mixture of4-(2-fluoro-5-methylsulfonylphenyl)-2-methylisoquinolin-1-one (150 mg,0.45 mmol) and trans-4-aminocyclohexan-1-ol (417 mg, 3.62 mmol) in NMP(0.2 mL) was heated for 20 min at 200-300° C. The cooled brownishresidue was purified by prep-HPLC to give the title compound (55.64 mg,28.8%) as a yellow solid. ¹H NMR (CDCl₃, 400 MHz): δ 8.54 (d, J=8.0 Hz,1H), 7.86 (dd, J₁=8.8 Hz, J₂=2.4 Hz, 1H), 7.66 (d, J=2.4 Hz, 1H),7.60-7.55 (m, 2H), 7.15-7.13 (m, 2H), 6.79 (d, J=8.8 Hz, 1H), 3.91-3.85(m, 1H), 3.67 (s, 3H), 3.63-3.55 (m, 1H), 3.37-3.34 (m, 1H), 3.06 (s,3H), 2.04-1.92 (m, 5H), 1.44-1.35 (m, 2H), 1.11-1.02 (m, 2H). LCMS(M+H)⁺: 427.1 (M+H)⁺.

Example 193:4-[2-(cyclopropylmethylamino)-5-ethylsulfonylphenyl]-2-methylisoquinolin-1-one

The title compound was prepared in a manner similar to Example 190 step2, by substituting 2-bromo-N-(cyclopropylmethyl)-4-ethylsulfonylanilinefor N-(2-bromo-4-methylsulfonylphenyl)oxolan-3-amine. ¹H NMR (CDCl₃, 400MHz): δ 8.51 (d, J=7.6 Hz, 1H), 7.80 (dd, J₁=8.8 Hz, J₂=2.0 Hz, 1H),7.61-7.51 (m, 3H), 7.15 (d, J=8.0 Hz, 1H), 7.13 (s, 1H), 6.76 (d, J=8.8Hz, 1H), 4.32 (t, J=4.8 Hz, 1H), 3.62 (s, 3H), 3.09 (q, J=7.2 Hz, 2H),3.01 (m, 2H), 1.29 (t, J=7.2 Hz, 3H), 0.95-0.89 (m, 1H), 0.46-0.38 (m,2H), 0.12-0.05 (m, 2H). LCMS (M+H)⁺: 397.1 (M+H)⁺.

Example 194:4-[2-(cyclopropylmethylamino)-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one

The title compound was prepared in a manner similar to Example 190 step2, by substituting 2-bromo-N-(cyclopropylmethyl)-4-methylsulfonylanilinefor N-(2-bromo-4-methylsulfonylphenyl)oxolan-3-amine. ¹H NMR (CDCl₃, 400MHz) δ 8.54 (d, J=7.6 Hz, 1H), 7.80 (dd, J₁=8.8 Hz, J₂=2.4 Hz, 1H), 7.67(d, J=2.4 Hz, 1H), 7.60-7.55 (m, 2H), 7.17 (d, J=8.0 Hz, 1H), 7.15 (s,1H), 6.77 (d, J=8.8 Hz, 1H), 4.24-4.23 (m, 1H), 3.66 (s, 3H), 3.06 (s,3H), 3.03-2.99 (m, 2H), 0.93-0.91 (m, 1H), 0.45-0.37 (m, 2H), 0.12-0.054(m, 2H). LCMS (M+H)⁺: 383.1 (M+H)⁺.

Example 195:4-[2-(cyclopropylmethylamino)-5-ethylsulfonylphenyl]-7-fluoro-2-methylisoquinolin-1-oneStep 1:7-fluoro-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1-one

A mixture of compound 4-bromo-7-fluoro-2-methylisoquinolin-1-one (1.2 g,4.69 mmol), bis(pinacolato)diboron (2.38 g, 9.37 mmol), AcOK (1.38 g,14.07 mmol), Pd₂(dba)₃ (429 mg, 0.47 mmol) and X-phos (224 mg, 0.47mmol) in dioxane (20 mL) was stirred at 70° C. for 18 hr under N₂. Themixture was concentrated and the residue was purified by CC to give thetitle compound (0.8 g, yield: 56.3%). ¹H NMR (CDCl₃, 400 MHz): δ 8.42(dd, J₁=9.2 Hz, J₂=4.2 Hz, 1H), 8.06 (dd, J₁=9.2 Hz, J₂=2.8 Hz, 1H),7.65 (s, 1H), 7.42-7.35 (m, 1H), 3.64 (s, 3H), 1.38 (s, 12H). LCMS(M+H)⁺: 304.1 (M+H)⁺.

Step 2:4-[2-(cyclopropylmethylamino)-5-ethylsulfonylphenyl]-7-fluoro-2-methylisoquinolin-1-one

The title compound was prepared in a manner similar to Example 193, bysubstituting7-fluoro-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1-onefor2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1-one.¹H NMR (CDCl₃, 400 MHz): δ 8.17 (d, J=8.4 Hz, 1H), 7.82 (d, J=8.4 Hz,1H), 7.61 (s, 1H), 7.38-7.29 (m, 1H), 7.21-7.13 (m, 1H), 7.11 (s, 1H),6.77 (d, J=8.4 Hz, 1H), 3.67 (s, 3H), 3.11 (q, J=7.2 Hz, 2H), 3.01 (d,J=6.8 Hz, 2H), 1.31 (t, J=7.2 Hz, 3H), 0.99-0.85 (m, 1H), 0.51-0.36 (m,2H), 0.17-0.02 (m, 2H). LCMS (M+H)⁺: 415.1 (M+H)⁺.

Example 196:4-[2-(cyclopropylmethylamino)-5-methylsulfonylphenyl]-7-fluoro-2-methylisoquinolin-1-one

The title compound was prepared in a manner similar to Example 195, bysubstituting 2-bromo-N-(cyclopropylmethyl)-4-methylsulfonylaniline for2-bromo-N-(cyclopropylmethyl)-4-ethylsulfonylaniline in step 2. ¹H NMR(CDCl₃, 400 MHz): δ 8.19 (dd, J₁=9.2 Hz, J₂=2.8 Hz, 1H), 7.86 (dd,J₁=8.8 Hz, J₂=2.0 Hz, 1H), 7.66 (d, J=2.4 Hz, 1H), 7.37-7.30 (m, 1H),7.18 (dd, J₁=8.8 Hz, J₂=4.8 Hz, 1H), 7.11 (s, 1H), 6.77 (d, J=8.8 Hz,1H), 4.14 (s, 1H), 3.68 (s, 3H), 3.06 (s, 3H), 3.01 (d, J=6.8 Hz, 2H),0.98-0.84 (m, 1H), 0.51-0.37 (m, 2H), 0.16-0.02 (m, 2H). LCMS (M+H)⁺:401.1 (M+H)⁺.

Example 197:4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methyl-6-(trifluoromethoxy)isoquinolin-1-one

A mixture of 4-bromo-2-methyl-6-(trifluoromethyl)isoquinolin-1-one (40mg, 0.13 mmol),2-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(46 mg, 0.13 mmol), K₃PO₄ (68 mg, 0.33 mmol) and Pd(dppf)Cl₂ (10 mg,0.01 mmol) in dioxane (0.9 mL) and H₂O (0.09 mL) was degassed with N₂for 10 min and then stirred at 60° C. for 1.6 hr. The rxn mixture wasdiluted with EtOAc (5 mL), dried over Na₂SO₄, filtered and concentratedunder reduced pressure. The residue was purified by normal phase silicagel CC to give the title compound (27 mg, 46%). ¹H NMR (DMSO-d6, 400MHz): δ 8.51 (d, J₁=8.4 Hz, 1H), 8.0 (dd, J₁=8.7 Hz, J₂=2.5 Hz, 1H),7.87 (s, 1H), 7.85 (m, 1H), 7.72 (s, 1H), 7.39 (m, 2H), 4.02 (m, 1H),3.86 (m, 1H), 3.61 (s, 3H), 3.23 (s, 3H), 0.90 (m, 1H), 0.31 (m, 2H),0.09 (m, 2H). LCMS (M+H)⁺: 452.2.

Example 198:4-(2-(cyclopropylmethoxy)-5-(methylsulfonyl)phenyl)-6-methoxy-2-methylisoquinolin-1(2H)-one

The title compound of Example 90, step 2 (30 mg, 0.075 mmol) inN,N-dimethyl-acetamide was treated with excess 25% sodium methoxide inmethanol and heated at 85° C. until complete. Silica gel chromatography(40-80% EA in hexane over 8 min, then isocratic) gave the title compound23 mg, 0.056 mmol, 74%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δppm 0.06-0.20 (m, 2H) 0.27-0.43 (m, 2H) 0.83-1.05 (m, 1H) 3.22 (s, 3H)3.53 (s, 3H) 3.73 (s, 3H) 3.83-4.16 (m, 2H) 6.47 (s, 1H) 7.04-7.20 (m,1H) 7.36 (d, J=8.59 Hz, 1H) 7.50 (s, 1H) 7.81 (s, 1H) 7.96 (d, J=6.82Hz, 1H) 8.23 (d, J=8.59 Hz, 1H). LCMS: 414 (M+H)⁺.

Example 199:4-[3-(cyclopropylmethoxy)-6-methylsulfonylpyridin-2-yl]-2-methylisoquinolin-1-oneStep 1: 6-methylsulfonylpyridin-3-ol

A mixture of 6-chloropyridin-3-ol (2.00 g, 15.44 mmol), MeSO₂Na (2.36 g,23.16 mmol), CuI (882.16 mg, 4.63 mmol), L-proline (533.28 mg, 4.63mmol), and K₂CO₃ (640.19 mg, 4.63 mmol) in DMSO (20 mL) were chargedinto a microwave tube. The sealed tube was heated at 140° C. for 3 hrunder microwave. After cooling to room temp, H₂O (100 mL) was added. Themixture was extracted with EtOAc (100 mL×3). The combined organic layerswere washed with brine (100 mL), dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified by CC togive the title compound (1.2 g, 44.8%) as a yellow solid. ¹H NMR(Methanol-d₄, 400 MHz): δ 8.24 (d, J=2.4 Hz, 1H), 7.94 (d, J=8.4 Hz,1H), 7.37 (dd, J₁=8.8 Hz, J₂=2.8 Hz, 1H), 3.15 (s, 3H).

Step 2: 2-iodo-6-methylsulfonylpyridin-3-ol and4-iodo-6-methylsulfonylpyridin-3-ol

A mixture of the title compound from Step 1 (3.0 g, 17.34 mmol), I₂ (6.6g, 26.01 mmol), NaHCO₃ (2.2 g, 26.20 mmol) and KI (0.72 g, 4.34 mmol) inTHF (30 mL) and H₂O (30 mL) was stirred at 60° C. for 18 hr. H₂O (100mL) was added and the mixture was extracted with EtOAc (100 mL×3). Thecombined organic layers were washed with brine (100 mL), dried overNa₂SO₄, filtered and concentrated under reduced pressure. The residuewas purified by preparative HPLC to give4-iodo-6-methylsulfonylpyridin-3-ol (700.0 mg) and2-iodo-6-methylsulfonylpyridin-3-ol (700.0 mg).2-iodo-6-methylsulfonylpyridin-3-ol: ¹H NMR (CDCl₃, 400 MHz): δ 12.08(brs, 1H), 7.86 (d, J=8.4 Hz, 1H), 7.31 (d, J=8.4 Hz, 1H), 3.19 (s, 3H).4-iodo-6-methylsulfonylpyridin-3-ol: ¹H NMR (CDCl₃, 400 MHz): δ 12.0(brs, 1H), 8.24 (s, 1H), 8.17 (s, 1H), 3.20 (s, 3H).

Step 3: 3-(cyclopropylmethoxy)-2-iodo-6-methylsulfonylpyridine

A mixture of 2-iodo-6-methylsulfonylpyridin-3-ol (500.0 mg, 1.67 mmol),bromomethylcyclopropane (248.4 mg, 1.84 mmol) and K₂CO₃ (461.3 mg, 33.4mmol) in ACN (15 mL) was stirred at 80° C. for 4 hr. H₂O (30 mL) wasadded and the mixture was extracted with EtOAc (30 mL×3). The combinedorganic layers were washed with brine (30 mL), dried over Na₂SO₄,filtered and concentrated to give the title compound (500.0 mg, 84.8%).¹H NMR (CDCl₃, 400 MHz): δ 7.96 (d, J=8.8 Hz, 1H), 7.52 (d, J=8.4 Hz,1H), 4.09 (d, J=6.8 Hz, 2H), 3.22 (s, 3H), 1.36-1.22 (m, 1H), 0.69-0.57(m, 2H), 0.43-0.37 (m, 2H). LCMS: 354.0 (M+1)⁺.

Step 4

A mixture of 3-(cyclopropylmethoxy)-2-iodo-6-methylsulfonylpyridine(140.0 mg, 0.40 mmol),2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1-one(136.5 mg, 0.48 mmol), K₃PO₄ (252.7 mg, 1.19 mmol) and Pd(dppf)Cl₂ (29.2mg, 0.04 mmol) in dioxane (5 mL) and H₂O (1 mL) was stirred at 70° C.for 18 hr under N₂. The mixture was filtered and concentrated. Theresidue was purified by prep-HPLC to give the title compound (81.0 mg,53.1%). ¹H NMR (CDCl₃, 400 MHz): δ 8.33 (dd, J₁=8.4 Hz, J₂=1.2 Hz, 1H),8.07 (d, J=8.4 Hz, 1H), 7.83 (d, J=8.8 Hz, 1H), 7.74 (s, 1H), 7.67 (t,J=8.4 Hz, 1H), 7.55 (t, J=8.4 Hz, 1H), 7.39 (d, J=8.0 Hz, 1H), 4.01 (d,J=6.8 Hz, 2H), 3.60 (s, 3H), 3.25 (s, 3H), 1.10-0.98 (m, 1H), 0.45-0.37(m, 2H), 0.23-0.17 (m, 2H). LCMS: 385.1 (M+1)⁺.

Example 200:4-[5-(cyclopropylmethoxy)-2-methylsulfonylpyridin-4-yl]-2-methylisoquinolin-1-oneStep 1: 5-(cyclopropylmethoxy)-4-iodo-2-methylsulfonylpyridine

The title compound was prepared in a manner similar to Example 199 Step3, by substituting 4-iodo-6-methylsulfonylpyridin-3-ol for2-iodo-6-methylsulfonylpyridin-3-ol. ¹H NMR (CDCl₃, 400 MHz): δ 8.35 (s,1H), 8.32 (s, 1H), 4.20 (d, J=7.2 Hz, 2H), 3.23 (s, 3H), 1.36-1.25 (m,1H), 0.67-0.58 (m, 2H), 0.44-0.37 (m, 2H). LCMS: 354.0 (M+1)⁺.

Step 2:4-[5-(cyclopropylmethoxy)-2-methylsulfonylpyridin-4-yl]-2-methylisoquinolin-1-one

The title compound was prepared in a manner similar to Example 199 Step4, by substituting5-(cyclopropylmethoxy)-4-iodo-2-methylsulfonylpyridine for3-(cyclopropylmethoxy)-2-iodo-6-methylsulfonylpyridine. ¹H NMR (CDCl₃,400 MHz): δ 8.66 (s, 1H), 8.31 (d, J=8.0 Hz, 1H), 7.96 (s, 1H),7.70-7.66 (m, 2H), 7.57-7.54 (t, J=7.2 Hz, 1H), 7.22 (d, J=8.0 Hz, 1H),4.12 (d, J=6.8 Hz, 2H), 3.57 (s, 3H), 3.28 (s, 3H), 1.05-0.92 (m, 1H),0.43-0.27 (m, 2H), 0.18-0.10 (m, 2H). LCMS: 385.1 (M−1)⁺.

Example 201:4-[3-(cyclopropylmethoxy)-6-methylsulfonylpyridin-2-yl]-7-fluoro-2-methylisoquinolin-1-one

The title compound was prepared in a manner similar to Example 199 Step4, by substituting7-fluoro-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1-onefor2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1-one.¹H NMR (DMSO-d6, 400 MHz): δ 8.07 (d, J=8.4 Hz, 1H), 7.97 (d, J=7.6 Hz,1H), 7.83 (d, J=8.4 Hz, 1H), 7.75 (s, 1H), 7.65-7.45 (m, 2H), 4.01 (d,J=6.4 Hz, 2H), 3.61 (s, 3H), 3.25 (s, 3H), 1.11-0.98 (m, 1H), 0.48-0.35(m, 2H), 0.27-0.15 (m, 2H). LCMS: 403.1 (M+1)⁺.

Example 202:4-[3-(cyclopropylmethoxy)-6-methylsulfonylpyridin-2-yl]-6-fluoro-2-methylisoquinolin-1-one

The title compound was prepared in a manner similar to Example 199 Step4, by substituting6-fluoro-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1-onefor2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1-one.¹H NMR (DMSO-d₆, 400 MHz): δ 8.37 (dd, J₁=8.8 Hz, J₂=6.4 Hz, 1H), 8.07(d, J=8.4 Hz, 1H), 7.84 (s, 1H), 7.82 (d, J=8.8 Hz, 1H), 7.45-7.36 (td,J₁=10.8 Hz, J₂=2.4 Hz, 1H), 7.18 (dd, J₁=10.8 Hz, J₂=2.4 Hz, 1H), 4.03(d, J=7.2 Hz, 2H), 3.59 (s, 3H), 3.25 (s, 3H), 1.15-1.03 (m, 1H),0.48-0.39 (m, 2H), 0.28-0.20 (m, 2H). LCMS: 403.1 (M+1)⁺.

Example 203:4-[5-(cyclopropylmethoxy)-2-methylsulfonylpyridin-4-yl]-7-fluoro-2-methylisoquinolin-1-one

The title compound was prepared in a manner similar to Example 200 Step2, by substituting7-fluoro-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1-onefor2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1-one.¹H NMR (DMSO-d6, 400 MHz): δ 8.08 (d, J=8.4 Hz, 1H), 7.97 (dd, J₁=9.2Hz, J₂=2.8 Hz, 1H), 7.83 (d, J=8.4 Hz, 1H), 7.75 (s, 1H), 7.62-7.55 (td,J₁=9.2 Hz, J₂=2.4 Hz, 1H), 7.50 (dd, J₁=9.2 Hz, J₂=5.2 Hz, 1H), 4.01 (d,J=6.8 Hz, 2H), 3.61 (s, 3H), 3.25 (s, 3H), 1.11-0.99 (m, 1H), 0.46-0.39(m, 2H), 0.24-0.18 (m, 2H). LCMS: 403.2 (M+1)⁺.

Example 204:4-(2-ethoxy-5-ethylsulfonylthiophen-3-yl)-2-methylisoquinolin-1-one

A mixture of 3-bromo-2-ethoxy-5-ethylsulfonylthiophene (18.0 mg, 0.06mmol),2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1-one(24 mg, 0.08 mmol), K₃PO₄ (42 mg, 0.20 mmol) and Pd(dppf)Cl₂ (6 mg,0.008 mmol) in dioxane (0.5 mL) and H₂O (0.05 mL) was stirred at 60° C.for 1.5 hr. The rxn mixture was then poured over H₂O (6 mL) andextracted with EtOAc (2×5 mL). The combined organic layers were driedover Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue was purified by normal phase silica gel CC to give the titlecompound (10.5 mg, 46%). ¹H NMR (DMSO-d₆, 400 MHz): δ 8.29 (d, J=7.9 Hz,1H), 7.71 (dd, J=7.6, 7.6 Hz, 1H), 7.57 (m, 3H), 7.35 (d, J=7.9 Hz, 1H),4.25 (m, 2H), 3.54 (s, 3H), 3.38 (m, 2H), 1.24 (m, 6H). LCMS: 378.05(M+1)⁺.

Example 205:4-[2-(cyclopropylmethylamino)-5-ethylsulfonylthiophen-3-yl]-2-methylisoquinolin-1-one

The title compound was prepared in a manner similar to Example 204, bysubstituting3-bromo-N-(cyclopropylmethyl)-5-ethylsulfonylthiophen-2-amine for3-bromo-2-ethoxy-5-ethylsulfonylthiophene. ¹H NMR (DMSO-d6, 400 MHz): δ8.30 (d, J=8.0 Hz, 1H), 7.70 (m, 1H), 7.53 (dd, J=7.6, 7.6 Hz, 1H), 7.5(s, 1H), 7.32 (s, 1H), 7.26 (d, J=8.0 Hz, 1H), 6.91 (m, 1H), 3.53 (s,3H), 3.25 (m, 2H), 2.95 (m, 2H), 1.20 (dd, J=7.3, 7.3 Hz, 3H), 1.05 (m,1H), 0.43 (m, 2H), 0.18 (m, 2H). LCMS: 403.1 (M+1)⁺.

Example 206:4-[3-(cyclopropylmethoxy)-6-ethylsulfonylpyridin-2-yl]-2-methylisoquinolin-1-oneStep 1: 5-bromo-2-ethylsulfanylpyridine

To a soln of 2,5-dibromopyridine (25 g, 105.5 mmol) in anhydrous DMSO(50 mL) at room temp was added NaSEt (13.3 g, 158.3 mmol) in oneportion. The mixture was stirred for 18 hr. It was then diluted with H₂O(500 mL) and extracted with EtOAc (200 mL×3). The combined organiclayers were washed by brine and dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified by CC(PE:EA=20:1˜10:1) to afford the title compound as light yellow oil (21 gyield: 91.3%). ¹H NMR (CDCl₃, 400 MHz): δ 8.49 (dd, J₁=2.0 Hz, J₂=0.4Hz, 1H), 7.59 (dd, J₁=8.8 Hz, J₂=2.4 Hz, 1H), 7.08 (dd, J₁=8.4 Hz,J₂=0.8 Hz, 1H), 3.16 (q, J=7.2 Hz, 2H), 1.38 (t, 3H). LCMS: 217.8(M+1)⁺; 219.8.

Step 2: 5-bromo-2-ethylsulfonylpyridine

To a soln of the title compound form Step 1 (21 g, 96.3 mmol) in DCM(200 mL) was added m-CPBA (58.2 g, 289 mmol, 85% purity) slowly at 0° C.and then stirred at 20° C. for 3 hr. The rxn mixture was quenched withsat. aq Na₂SO₃ (200 mL) and then extracted with DCM (200 mL×2). Thecombined organic layers were washed with sat. aq NaHCO₃ (200 mL), H₂O(200 mL), and brine (200 mL), dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give 22 g of crude (˜90% purity)title compound as a white solid that was used in the next step withoutfurther purification. ¹H NMR (CDCl₃, 400 MHz): δ 8.82 (d, J=2.0 Hz, 1H),8.13 (dd, J₁=8.4 Hz, J₂=2.0 Hz, 1H), 8.01 (d, J=8.0 Hz), 3.43 (q, J=7.2Hz, 2H), 1.33 (t, J=7.2 Hz, 3H). LCMS: 249.8 (M+1)⁺; 251.8.

Step 3: 2-ethylsulfonyl-5-methoxypyridine

To a soln of the title compound form Step 2 (21 g, 84 mmol) in MeOH (150mL) was added MeONa (11.3 g, 210 mmol). The mixture was refluxed for 5hr, then cooled to room temp and concentrated under reduced pressure.The residue was triturated with isopropyl ether and filtered. Thefiltrate was concentrated under reduced pressure to give the titlecompound (4.5 g, yield, 23% two steps) as yellow oil. ¹H NMR (CDCl₃, 400MHz): δ 8.42 (d, J=2.8 Hz, 1H), 8.07 (d, J=8.4 Hz 1H), 7.37 (dd, J₁=8.8Hz, J₂=2.8 Hz, 1H), 3.97 (s, 1H), 3.38 (q, J=7.2 Hz, 2H), 1.30 (t, J=7.2Hz, 3H).

Step 4: 6-ethylsulfonylpyridin-3-ol

The title compound form Step 3 (4.5 g, 22.4 mmol) and pyridiniumhydrochloride (26 g, 224 mmol) was heated to 160° C. for 4 hr. It wascooled to room temp, diluted with H₂O (100 mL) and extracted with EtOAc(100 mL×3). The combined organic layers were washed with brine (200 mL),dried over Na₂SO₄ and concentrated. The residue was purified by CC toafford the title compound (3 g, 72%) as a yellow solid. ¹H NMR (DMSO-d6,400 MHz): δ 8.87 (s, 1H), 8.86 (s, 1H), 8.45 (d, J=8.4 Hz, 1H), 7.93(dd, J₁=8.8 Hz, J₂=2.4 Hz, 1H), 3.82 (q, J=7.2 Hz, 2H), 1.72 (t, J=7.2Hz, 3H). LCMS: 187.9 (M+1)⁺.

Step 5: 6-ethylsulfonyl-2-iodopyridin-3-ol and6-ethylsulfonyl-4-iodopyridin-3-ol

To a soln of the title compound from Step 4 (3 g, 16 mmol) in a mixtureof THF (20 mL) and H₂O (20 mL) was added KI (662 mg, 4 mmol) and iodine(6.1 g, 24 mmol). The rxn was stirred at room temp for 1 hr and thenheated to 60° C. for another 17 hr. The rxn mixture was then cooled toroom temp and concentrated under reduced pressure to remove the THF. Themixture was diluted with H₂O (100 mL) and extracted with DCM (10 mL×3).The combined organic layers were washed with brine, dried over Na₂SO₄,filtered and concentrated. The residue was purified by prep-HPLC toafford 6-ethylsulfonyl-2-iodopyridin-3-ol and6-ethyl-sulfonyl-4-iodopyridin-3-ol as white solids.6-ethylsulfonyl-2-iodopyridin-3-ol: ¹H NMR (DMSO-d₆, 400 MHz): δ 7.85(d, J=8.4 Hz, 1H), 7.31 (d, J=8.4 Hz, 1H), 3.30 (q, J=7.2 Hz, 2H), 1.11(t, J=7.2 Hz 3H). LCMS: 313.8 (M+1)⁺;6-ethylsulfonyl-4-iodopyridin-3-ol: ¹H NMR (DMSO-d₆, 400 MHz) δ 8.23 (s,1H), 8.18 (s, 1H), 3.31 (q, J=7.2 Hz, 2H, overlapped with solvent peak),1.10 (t, J=7.2 Hz 3H). LCMS: 313.8 (M+1)⁺.

Step 6: 3-(cyclopropylmethoxy)-6-ethylsulfonyl-2-iodopyridine

The title compound was prepared in a manner similar to Example 199 Step3, by substituting 6-ethylsulfonyl-2-iodopyridin-3-ol for2-iodo-6-methylsulfonylpyridin-3-ol. ¹H NMR (CDCl₃, 400 MHz): δ 7.98 (d,J=8.4 Hz, 1H), 7.06 (d, J=8.4 Hz 1H), 4.02 (d, J=6.8 Hz 2H), 3.40 (q,J=7.2 Hz, 2H), 1.38-1.26 (m, 4H), 0.77-0.73 (m, 2H), 0.49-0.46 (m, 2H).LCMS: 367.8 (M−1)⁺.

Step 7:4-[3-(cyclopropylmethoxy)-6-ethylsulfonylpyridin-2-yl]-2-methylisoquinolin-1-one

To a soln of the title compound from Step 6 (45 mg, 0.12 mmol) and2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1-one(50 mg, 0.16 mmol) in dioxane (2.5 mL) and H₂O (0.5 mL) was addedPd(dppf)Cl₂ (9 mg, 0.013 mmol) and K₃PO₄ (86 mg, 0.4 mmol) in oneportion at room temp under N₂. The mixture was stirred for 12 hr at 90°C. under N₂. H₂O (15 mL) was added and the mixture was extracted withDCM (30 mL×3). The combined organic phases were dried over Na₂SO₄,filtered, concentrated under reduced pressure. The residue was purifiedby prep-HPLC to give the title compound (16 mg, yield: 32%) as a whitesolid. ¹H NMR (CDCl₃, 400 MHz) δ 8.52 (d, J=7.6 Hz, 1H), 8.11 (d, J=8.8Hz 1H), 7.61-7.56 (m, 1H), 7.53-7.49 (m, 1H), 7.42 (d, J=8.8 Hz 1H),7.38 (s, 1H), 7.34 (d, J=7.6 Hz 1H), 3.92 (d, J=7.2 Hz 2H), 3.68 (s,3H), 3.41 (q, J=6.8 Hz, 2H), 1.33 (t, 3H), 1.08-1.02 (m, 1H), 0.54-0.48(m, 2H), 0.22-0.21 (m, 2H). LCMS: 399.1 (M+1)⁺.

Example 207:4-[5-(cyclopropylmethoxy)-2-ethylsulfonylpyridin-4-yl]-2-methylisoquinolin-1-oneStep 1: 5-(cyclopropylmethoxy)-2-ethylsulfonyl-4-iodopyridine

The title compound was prepared in a manner similar to Example 199 Step3, by substituting 6-ethylsulfonyl-4-iodopyridin-3-ol for2-iodo-6-methylsulfonylpyridin-3-ol. ¹H NMR (CDCl₃, 400 MHz) δ 8.48 (s,1H), 8.11 (s, 1H), 4.12 (d, J=6.8 Hz 2H), 3.37 (q, J=7.6 Hz, 2H),1.39-1.27 (m, 4H), 0.76-0.73 (m, 2H), 0.48-0.46 (m, 2H). LCMS: 367.8(M+1)⁺.

Step 2:4-[5-(cyclopropylmethoxy)-2-ethylsulfonylpyridin-4-yl]-2-methylisoquinolin-1-one

The title compound was prepared in a manner similar to Example 206 Step7, by substituting 6-ethylsulfonyl-4-iodopyridin-3-ol for3-(cyclopropylmethoxy)-6-ethylsulfonyl-2-iodopyridine. ¹H NMR (CDCl₃,400 MHz): δ 8.54-8.52 (m, 1H), 8.45 (s, 1H), 8.05 (s, 1H), 7.63-7.58 (m,1H), 7.56-7.52 (m, 1H), 7.16 (d, J=8.8 Hz 1H), 4.01 (d, J=7.2 Hz 2H),3.68 (s, 3H), 3.44 (q, J=7.2 Hz, 2H), 1.36 (t, 3H), 1.09-1.05 (m, 1H),0.50-0.48 (m, 2H), 0.19-0.18 (m, 2H). LCMS: 399.1 (M+1)⁺.

Example 208:4-[5-(2-hydroxyethylsulfonyl)-2-methoxyphenyl]-2-methyl-6-(1-methylpyrazol-4-yl)isoquinolin-1-oneStep 1: 2-(4-methoxyphenyl)sulfanylethyl acetate

4-methoxybenzene-1-thiol (15.7 g, 0.11 mol), 2-bromoethyl acetate (18.8g, 0.11 mol), and K₂CO₃ (46.6 g, 0.34 mol) in acetone (200 mL) werestirred at room temp for 12 hr. Then the mixture was filtered. AfterCH₂Cl₂ extractive work-up and silica gel chromatography (PE:EA=1:0˜10:1)the title compound (21.1 g, 83.3%) was obtained as a colorless oil. ¹HNMR (CDCl₃, 400 MHz): δ 7.40 (dd, J₁=6.8 Hz, J₂=2.0 Hz, 2H), 6.86 (dd,J₁=6.8 Hz, J₂=2.0 Hz, 2H), 4.18 (t, J=7.2 Hz, 2H), 3.80 (s, 3H), 3.02(t, J=7.2 Hz, 2H), 2.03 (s, 3H). LCMS: 139.0 (M−87)⁺.

Step 2: 2-(4-methoxyphenyl)sulfonylethyl acetate

m-CPBA (80.3 g, 467 mmol) was added to the title compound of step 1(21.1 g, 93.4 mmol) in CH₂Cl₂ (500 mL). After stirring at room temp for12 hr, the mixture was subjected to CH₂Cl₂ extractive work-up and silicagel chromatography (PE:EA=1:0-1:1) to give the title compound (20.0 g,83.3%) as a colorless oil. ¹H NMR (CDCl₃, 400 MHz): δ 7.85 (dd, J₁=6.8Hz, J₂=2.0 Hz, 2H), 7.04 (dd, J₁=6.8 Hz, J₂=2.0 Hz, 2H), 4.39 (t, J=6.0Hz, 2H), 3.90 (s, 3H), 3.43 (t, J=6.0 Hz, 2H), 1.89 (s, 3H). LCMS: 280.9(M+Na)⁺.

Step 3: 2-(3-bromo-4-methoxyphenyl)sulfonylethanol

Br₂ (25 g, 155.0 mmol) was added dropwise over 30 min to the titlecompound of step 2 (8.0 g, 31.0 mmol) in acetic acid (100 mL) at 0° C.The mixture was heated at 50° C. for 12 hr. Aq Na₂SO₃ (200 mL) was addedand the pH was adjusted to 8 with sat. aq NaHCO₃. The mixture wassubjected to EA extractive work-up and silica gel chromatography(PE:EA=1:0-1:1) to give the title compound (2.7 g, 27.3%) as a whitesolid. ¹H NMR (CDCl₃, 400 MHz): δ 8.11 (d, J=2.4 Hz, 1H), 7.87 (dd,J₁=8.8 Hz, J₂=2.4 Hz, 1H), 7.04 (d, J=2.4 Hz, 1H), 4.05-4.00 (m, 5H),3.34-3.67 (m, 3H). LCMS: 316.9, 318.9 (M+Na)⁺.

Step 4: 2-[2-(3-bromo-4-methoxyphenyl)sulfonylethoxy]oxane

To the title compound of step 3 (1.0 g, 3.4 mmol) in CH₂Cl₂ (10 mL) wasadded 3,4-dihydro-2H-pyran (1.4 g, 17.0 mmol) followed by pyridiniump-toluensulfonate (64.6 mg, 0.34 mmol). After stirring at room temp for12 hr, the mixture was subjected to CH₂Cl₂ extractive work-up and silicagel chromatography (PE:EA=1:0-5:1) to give the title compound (1.1 g,85.6%) as a yellow oil. ¹H NMR (CDCl₃, 400 MHz): δ 8.11 (d, J=2.4 Hz,1H), 7.86 (dd, J₁=8.8 Hz, J₂=2.4 Hz, 1H), 7.00 (d, J=8.8 Hz, 1H), 4.51(dd, J₁=4.0 Hz, J₂=2.4 Hz, 1H), 4.09-4.03 (m, 1H), 3.98 (s, 3H),3.84-3.79 (m, 1H), 3.79-3.74 (m, 1H), 3.50-3.46 (m, 1H), 3.45-3.42 (m,2H), 1.58-1.37 (m, 6H). LCMS: 401.0, 403.0 (M+Na)⁺.

Step 5:2-[2-methoxy-5-[2-(oxan-2-yloxy)ethylsulfonyl]phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

The title compound of step 4 (700 mg, 1.8 mmol),4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(938 mg, 3.6 mmol) Pd(dppf)Cl₂ (263 mg, 0.36 mmol) and AcOK (1.05 g,10.8 mmol) in 1,4-dioxane (7 mL) was stirred at 70° C. for 12 hr. Aftersilica gel CC (PE:EA=1:0˜1:1) the title compound (300 mg, 39.2%) wasobtained as a yellow oil. ¹H NMR (CDCl₃, 400 MHz): δ 8.20 (d, J=2.4 Hz,1H), 7.94 (dd, J₁=8.8 Hz, J₂=2.8 Hz, 1H), 6.95 (d, J=8.8 Hz, 1H), 4.52(t, J=4.0 Hz, 1H), 4.08-4.01 (m, 2H), 3.91 (s, 3H), 3.82-3.74 (m, 2H),3.43 (t, J=2.4 Hz, 2H), 1.58-1.42 (m, 6H), 1.35 (s, 12H). LCMS: 343.0(M+H-THP)⁺.

Step 6:4-[2-methoxy-5-[2-(oxan-2-yloxy)ethylsulfonyl]phenyl]-2-methyl-6-(1-methylpyrazol-4-yl)isoquinolin-1-one

The title compound of step 5 (325 mg, 0.76 mmol), the title compound ofExample 41, step 2 (201 mg, 0.64 mmol), Pd(dppf)Cl₂ (66 mg, 0.08 mmol)and AcOK (125 mg, 1.28 mmol) in 1,4-dioxane (6 mL) were heated at 70° C.for 12 hr. After silica gel CC (PE:EA=5:1˜0:1) the title compound (80mg, 23.6%) was obtained as a gray solid. ¹H NMR (CDCl₃, 400 MHz): δ 8.48(d, J=8.4 Hz, 1H), 8.03 (dd, J₁=8.8 Hz, J₂=2.4 Hz, 1H), 7.88 (d, J=2.4Hz, 1H), 7.58-7.69 (m, 2H), 7.14-7.18 (m, 2H), 7.06 (s, 1H), 4.50 (t,J=4.4 Hz, 2H), 4.06-4.15 (m, 1H), 3.93 (s, 3H), 3.84-3.90 (m, 1H), 3.84(s, 3H), 3.71-3.80 (m, 2H), 3.65 (s, 3H), 3.49 (t, J=5.6 Hz, 2H),3.41-3.47 (m, 1H), 1.25-1.67 (m, 6H). LCMS: 538.2 (M+H)⁺; 454.1(M+H-THP)⁺.

Step 7:4-[5-(2-hydroxyethylsulfonyl)-2-methoxyphenyl]-2-methyl-6-(1-methylpyrazol-4-yl)isoquinolin-1-one

The title compound of step 6 (80 mg, 0.15 mmol) and pyridiniump-toluensulfonate (59 mg, 0.31 mmol) in DCM (2 mL) were stirred at roomtemp for 5 hr. After purification by prep-TLC (DCM:MeOH=10:1), the titlecompound (16.47 mg, 24.4%) was obtained as an off-white solid. ¹H NMR(CDCl₃, 400 MHz): δ 8.49 (d, J=8.4 Hz, 1H), 8.05 (dd, J₁=8.8 Hz, J₂=2.4Hz, 1H), 7.88 (d, J=2.4 Hz, 1H), 7.68 (s, 1H), 7.59-7.62 (m, 2H), 7.20(d, J=8.8 Hz, 1H), 7.12 (d, J=1.2 Hz, 1H), 7.07 (s, 1H), 4.03-4.11 (m,2H), 3.94 (s, 3H), 3.86 (s, 3H), 3.66 (s, 3H), 4.16 (t, J=5.2 Hz, 2H),2.72 (t, J=6.4 Hz, 1H). LCMS: 454.1 (M+H)⁺.

Example 209:N-[4-(cyclopropylmethoxy)-2-fluoro-5-[2-methyl-6-(1-methylpyrazol-4-yl)-1-oxoisoquinolin-4-yl]phenyl]ethanesulfonamide

The title compound was prepared in 4 steps in a similar manner asExample 86 except that the alkoxide of cyclopropylmethanol wassubstituted for sodium methoxide in step 1. ¹H NMR (DMSO-d₆, 400 MHz): δ9.46 (s, 1H), 8.26 (d, J=8.4 Hz, 1H), 8.17 (s, 1H), 7.84 (s, 1H), 7.34(d, J=8.0 Hz, 1H), 7.42 (s, 1H), 7.27-7.25 (m, 1H), 7.16 (d, J=12.4 Hz,1H), 3.97-3.96 (m, 2H, overlapped with solvent peak), 3.85 (s, 3H), 3.54(s, 3H), 3.13-3.07 (m, 2H), 1.30-1.26 (m, 2H), 0.91-0.90 (m, 1H),0.27-0.22 (m, 2H), 0.04-0.09 (m, 2H). LCMS: 511.1 (M+1)⁺.

Example 210:4-(5-ethylsulfonyl-2-methoxyphenyl)-2-methyl-6-(1H-pyrazol-4-yl)isoquinolin-1-one

The title compound was prepared in a similar manner to Example 79 using4-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole instead of1-methyl-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. ¹H NMR(DMSO-d6, 400 MHz) δ 8.26 (d, J=8.4 Hz, 1H), 8.02 (s, 2H), 7.97-8.00 (m,1H), 7.75-7.79 (m, 2H), 7.50 (s, 1H), 7.42 (d, J=8.8 Hz, 1H), 7.16 (d,J=1.2 Hz, 1H), 3.82 (s, 3H), 3.54 (s, 3H), 3.31 (q, J=7.2, 2H), 1.13 (t,J=7.2 Hz, 3H). LCMS: 424.0 (M+1)⁺.

Example 211:4-(2-ethoxy-5-methylsulfonylphenyl)-2-methyl-6-(1-methylpyrazol-4-yl)isoquinolin-1-one

2-(2-ethoxy-5-methanesulfonylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolanewas prepared in a similar manner to Example 90, step 1 and coupled tothe title compound of Example 41, step 2 in a manner similar to Example90, step 2 to give the title compound. ¹H NMR (CDCl₃, 400 MHz) δ 8.48(d, J=8.4 Hz, 1H), 8.06-8.02 (m, 1H), 7.89 (d, J=2.8 Hz, 1H), 7.68 (s,1H), 7.62 (s, 1H), 7.61 (d, J=1.6 Hz, 1H), 7.18 (d, J=1.2 Hz, 1H), 7.14(d, J=8.8 Hz, 1H), 7.08 (s, 1H), 4.12 (q, J=7.2 Hz, 2H), 3.94 (s, 3H),3.66 (s, 3H), 3.12 (s, 3H), 1.17 (t, J=7.2 Hz, 3H). LCMS: 438.1 (M+1)⁺.

Example 212:2-methyl-6-(1-methylpyrazol-4-yl)-4-(5-methylsulfonyl-2-propoxyphenyl)isoquinolin-1-one

2-(5-methanesulfonyl-2-propoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolanewas prepared in a similar manner to Example 90, step 1 and coupled tothe title compound of Example 41, step 2 in a manner similar to Example90, step 2 to give the title compound. ¹H NMR (CDCl₃, 400 MHz): δ 8.49(d, J=8.4 Hz, 1H), 8.02 (s, J=6.8 Hz, 1H), 7.90 (d, J=2.4 Hz, 1H), 7.68(s, 1H), 7.61 (s, 1H), 7.60 (d, J=6.8 Hz, 1H), 7.18 (s, 1H), 7.15 (d,J=8.8 Hz, 1H), 7.08 (s, 1H), 4.00 (m, 2H) 3.93 (s, 3H), 3.66 (s, 3H),3.12 (s, 3H), 1.56 (m, 2H), 0.65 (t, J=7.2 Hz, 3H). LCMS: 452.0 (M+1)⁺.

Example 213:N-[2-[2-methyl-6-(1-methylpyrazol-4-yl)-1-oxoisoquinolin-4-yl]pyridin-4-yl]ethanesulfonamide

The title compound was prepared after 2-chloropyridin-4-amine wassufonylated with ethanesulfonyl chloride and the resulting product wascoupled to the title compound of Example 46, step 2. ¹H NMR (CDCl₃, 400MHz): δ 10.65 (brs, 1H), 8.56 (s, 1H), 8.29 (d, J=8.4 Hz, 1H), 8.22 (s,1H), 8.01-7.73 (m, 4H), 7.37 (s, 1H), 7.18 (s, 1H), 3.87 (s, 3H), 3.59(s, 3H), 1.25 (t, J=7.2 Hz, 3H). LCMS: 424.0 (M+1)⁺.

Example 214:[4-(cyclopropylmethoxy)-3-(2-methyl-1-oxoisoquinolin-4-yl)phenyl]sulfamateStep 1: [3-bromo-4-(cyclopropylmethoxy)phenyl]sulfamate

3-bromo-4-(cyclopropylmethoxy)phenol (970 mg, 4.0 mmol) and sulfamoylchloride (1.95 g, 16.0 mmol) in DMA (15 mL) were stirred at room tempfor 5 hr. Extractive work-up from EA and H₂O gave the title compound(1.0 g, yield: 78.0%) which was carried on without purification. ¹H NMR(CDCl₃, 400 MHz): δ 7.28 (d, J=2.8 Hz, 1H), 7.24 (dd, J₁=8.8 Hz, J₂=2.8Hz, 1H), 6.88 (d, J=8.8 Hz, 1H), 5.07 (s, 2H), 3.89 (d, J=6.8 Hz, 2H),1.35-1.25 (m, 1H), 0.70-0.63 (m, 2H), 0.43-0.36 (m, 2H). LCMS: 322.0(M+1)⁺.

Step 2:[4-(cyclopropylmethoxy)-3-(2-methyl-1-oxoisoquinolin-4-yl)phenyl]sulfamate

The title compound of step 1 (300 mg, 0.935 mmol), the title compound ofExample 89, step 1 (293 mg, 1.028 mmol), K₃PO₄ (595 mg, 2.805 mmol) andPd(dppf)Cl₂ (15 mg) in dioxane (5 mL) and H₂O (1 mL) were heated at 70°C. for 18 hr under N₂ whereupon it was discovered that the sulfamoylgroup had been cleaved to the phenol. HPLC purification gave the phenol(59 mg, 0.184 mmol) which was again treated with sulfamoyl chloride (100mg, 0.87 mmol) in DMA (3 mL) in a manner similar to step 1. PreparativeHPLC gave the title compound (64.21 mg, yield: 87.02%) as grey solid. ¹HNMR (CDCl₃, 400 MHz): δ 8.48 (d, J=8.0 Hz, 1H), 7.56 (t, J=7.6 Hz, 1H),7.49 (d, J=7.6 Hz, 1H), 7.35 (dd, J₁=9.2 Hz, J₂=2.4 Hz, 1H), 7.30-7.27(m, 1H), 7.26-7.22 (m, 1H), 7.04 (s, 1H), 6.98 (d, J=9.2 Hz, 1H), 5.14(s, 2H), 3.82-3.73 (m, 2H), 3.62 (s, 3H), 1.03-1.90 (m, 1H), 0.45-0.32(m, 2H), 0.13-0.03 (m, 2H). LCMS: 401.0 (M+1)⁺.

Example 215:[4-(cyclopropylmethoxy)-3-(1,5-dimethyl-6-oxopyridin-3-yl)phenyl]sulfamate

The title compound was prepared in a similar manner to Example 214, step2 except that1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2(1H)-pyridinone was substituted for the title compound of Example 89,step 1. ¹H NMR (CDCl₃, 400 MHz): δ 7.54 (d, J=2.0 Hz, 1H), 7.50 (s, 1H),7.23-7.18 (m, 2H), 6.92-6.87 (m, 1H), 5.20 (s, 2H), 3.84 (d, J=6.8 Hz,2H), 3.61 (s, 3H), 2.20 (s, 3H), 1.25-1.17 (m, 1H), 0.66-0.59 (m, 1H),0.36-0.29 (m, 1H). LCMS: 365.1 (M+1)⁺.

Example 216:4-(2-ethoxy-5-methylsulfonylphenyl)-2-methyl-5,6,7,8-tetrahydroisoquinolin-1-one

2-bromo-1-ethoxy-4-methanesulfonylbenzene was prepared in a similarmanner as Example 46, step 1 except that iodoethane was substituted for(chloromethyl)cyclopropane. The title compound of Example 163, step 3and 2-bromo-1-ethoxy-4-methanesulfonylbenzene were reacted in a similarmanner as in Example 89, step 2 to give the title compound. ¹H NMR(CDCl₃, 400 MHz): δ 7.92 (dd, J₁=8.8 Hz, J₂=2.0 Hz, 1H), 7.68 (d, J=2.0Hz, 1H), 7.03 (d, J=8.8 Hz, 1H), 6.69 (d, J=8.8 Hz, 1H), 4.20 (q, J=7.2Hz, 2H), 3.59 (s, 3H), 3.08 (s, 3H), 2.70-2.60 (m, 2H), 2.33-2.18 (m,2H), 1.65-1.61 (m, 4H), 1.45-1.02 (t, J=7.2 Hz, 3H). LCMS: 362.0 (M+H)⁺.

Example 217:4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methyl-5,6,7,8-tetrahydroisoquinolin-1-one

The title compound of Example 163, step 3 and2-bromo-1-(cyclopropylmethoxy)-4-methylsulfonylbenzene were reacted in asimilar manner as in Example 89, step 2 to give the title compound. ¹HNMR (CDCl₃, 400 MHz): δ 7.92 (dd, J₁=8.4 Hz, J₂=2.0 Hz, 1H), 7.70 (d,J=2.0 Hz, 1H), 7.06 (s, 1H), 7.02 (d, J=8.4 Hz, 1H), 3.92-3.87 (m, 2H),3.62 (s, 3H), 3.08 (s, 3H), 2.70-2.60 (m, 2H), 2.40-2.30 (m, 2H),1.77-1.64 (m, 4H), 1.21-1.17 (m, 1H), 0.63-0.61 (m, 2H), 0.29-0.27 (m,2H). LCMS: 388.1 (M+H)⁺.

Example 218:N-[4-(cyclopropylmethoxy)-2-fluoro-5-(2-methyl-1-oxo-5,6,7,8-tetrahydroisoquinolin-4-yl)phenyl]methanesulfonamide

N-[5-bromo-4-(cyclopropylmethoxy)-2-fluorophenyl]methanesulfonamide wasprepared in three steps in a similar manner as Example 86 except thatthe alkoxide of cyclopropylmethanol was substituted for sodium methoxidein step 1 and methanesulfonylchloride was substituted forethansulfonylchloride in step 3. The title compound of Example 163, step3 andN-[5-bromo-4-(cyclopropylmethoxy)-2-fluorophenyl]methanesulfonamide werereacted in a similar manner as in Example 89, step 2 to give the titlecompound. ¹H NMR (CDCl₃, 400 MHz): δ 7.29 (d, J=9.2 Hz, 1H), 6.96 (s,1H), 6.70 (d, J=12.0 Hz, 1H), 6.21 (s, 1H), 3.76-3.75 (m, 2H), 3.56 (s,3H), 3.02 (s, 3H), 2.70-2.60 (m, 2H), 2.36-2.17 (m, 2H), 1.80-1.70 (m,2H), 1.69-1.64 (m, 2H), 1.20-1.10 (m, 1H), 0.60-0.50 (m, 2H), 0.27-0.25(m, 2H). LCMS: 421.1 (M+H)⁺.

Example 219:4-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-2-methyl-5,6,7,8-tetrahydroisoquinolin-1-one

2-bromo-1-(cyclopropylmethoxy)-4-(ethanesulfonyl)benzene was prepared ina similar manner as Example 79, step 3 except that the alkoxide ofcyclopropylmethanol was substituted for sodium methoxide. The titlecompound of Example 163, step 3 and2-bromo-1-(cyclopropylmeth-oxy)-4-(ethanesulfonyl)benzene were reactedin a similar manner as in Example 89, step 2 to give the title compound.¹H NMR (DMSO-d6, 400 MHz): δ 7.83 (dd, J₁=8.8 Hz, J₂=2.4 Hz, 1H), 7.56(d, J=2.4 Hz, 1H), 7.43 (s, 1H), 7.65 (d, J=8.8 Hz, 1H), 4.02-3.90 (m,2H), 3.43 (s, 3H), 3.29-3.23 (m, 2H), 2.49-2.44 (m, 4H), 1.61-1.50 (m,4H), 1.15-1.08 (m, 5H), 0.53-0.51 (m, 2H), 0.29-0.27 (m, 2H). LCMS:402.0 (M+H)⁺.

Example 220:N-[2-(2-methyl-1-oxoisoquinolin-4-yl)-4-methylsulfonylphenyl]cyclopropanecarboxamide

2-bromo-4-methanesulfonylaniline was coupled to the title compound ofExample 89, step 1 in a manner similar to Example 89, step 2. Theresulting product was reacted with cyclopropanecarbonyl chloride usingdiisopropylethylamine in THF to prepare the title compound. ¹H NMR(CDCl₃, 400 MHz): δ 9.38 (s, 1H), 8.34 (d, J=8.0 Hz, 1H), 8.23 (d, J=8.8Hz, 1H), 7.96 (d, J=8.8 Hz, 1H), 7.83 (s, 1H), 7.53-7.64 (m, 3H), 6.94(d, J=8.0 Hz, 1H), 3.59 (s, 3H), 3.25 (m, 3H), 1.64 (brs, 1H), 0.52-0.75(m, 4H). LCMS: 397.0 (M+1)⁺.

Example 221:N-[2-(2-methyl-1-oxoisoquinolin-4-yl)-4-methylsulfonylphenyl]propanamide

The title compound was prepared in the same manner as Example 220 exceptthat propanoyl chloride was substituted for cyclopropanecarbonylchloride. ¹H NMR (CDCl₃, 400 MHz): δ 8.70 (d, J=8.8 Hz, 1H), 8.57 (d,J=6.4 Hz, 1H), 8.04 (dd, J=2.0, 8.8 Hz, 1H), 7.88 (d, J=2.0 Hz, 1H),7.55-7.65 (m, 2H), 7.19 (s, 1H), 7.01-7.20 (m, 2H), 3.67 (s, 3H), 3.11(s, 3H), 2.00-2.21 (m, 2H), 0.93 (t, J=7.2 Hz, 3H). LCMS: 385.0 (M+1)⁺.

Example 222:N-[2-(2-methyl-1-oxoisoquinolin-4-yl)-4-methylsulfonylphenyl]acetamide

The title compound was prepared in the same manner as Example 220 exceptthat acetyl chloride was substituted for cyclopropanecarbonyl chloride.¹H NMR (CDCl₃, 400 MHz): δ 8.67 (d, J=8.8 Hz, 1H), 8.51 (d, J=7.6 Hz,1H), 8.03 (dd, J=2.0, 6.8 Hz, 1H), 7.86 (d, J=2.0 Hz, 1H), 7.62-7.67 (m,1H), 7.57-7.62 (m, 1H), 7.36 (s, 1H), 7.16 (s, 1H), 7.07-7.10 (m, 1H),3.54 (s, 3H), 3.10 (s, 3H), 1.96 (s, 3H). LCMS: 371.0 (M+1)⁺.

Example 223:4-[2-(cyclopropylmethylamino)-5-methylsulfonylphenyl]-2-methyl-5,6,7,8-tetrahydroisoquinolin-1-one

The sulfonyl compound of Example 194 was coupled as described in Example163 to give the title compound. ¹H NMR (CDCl₃, 400 MHz): δ 7.89 (dd,J₁=8.8 Hz, J₂=2.4 Hz, 1H), 7.51 (d, J=2.4 Hz, 1H), 7.10 (s, 1H), 6.69(d, J=8.8 Hz, 1H), 3.62 (s, 3H), 3.04-3.02 (m, 5H), 2.67-2.62 (m, 2H),2.26-2.24 (m, 2H), 1.78-1.76 (m, 2H), 1.75-1.74 (m, 2H), 1.05-1.02 (m,1H), 0.58-0.54 (m, 2H), 0.23-0.21 (m, 2H). LCMS: 387.0 (M+H)⁺.

Example 224:8-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-6-methyl-2-(1-methylpyrazol-4-yl)pyrido[4,3-d]pyrimidin-5-oneStep 1: ethyl 4-methyl-2-(1-methylpyrazol-4-yl)pyrimidine-5-carboxylate

Ethyl 2-chloro-4-methylpyrimidine-5-carboxylate (1.0 g, 5.0 mmol),1-methyl-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.24 g,6.0 mmol), K₃PO₄ (3.18 mg, 15.0 mmol) and Pd(dppf)Cl₂ (100 mg) indioxane (15 mL) and H₂O (3 mL) were heated at 120° C. for 18 hr underN₂. Silica gel chromatography (PE:EA=3:1 to 1:1) gave the title compound(72 mg, yield: 32.0%). ¹H NMR (CDCl₃, 400 MHz): δ 9.08 (s, 1H), 8.22 (s,1H), 8.15 (s, 1H), 4.40 (q, J=7.2 Hz, 2H), 3.98 (s, 3H), 2.82 (s, 3H),1.42 (t, J=7.2 Hz, 3H). LCMS: 247.1 (M+1)⁺.

Step 2: ethyl4-[(E)-2-(dimethylamino)ethenyl]-2-(1-methylpyrazol-4-yl)pyrimidine-5-carboxylateand ethyl2-(1-methylpyrazol-4-yl)-4-[(E)-2-pyrrolidin-1-ylethenyl]pyrimidine-5-carboxylate

The title compound from step 1 (800 mg, 3.22 mmol), DMF-DMA (15.0 mL)and pyrrolidine (3.0 mL) were heated at 120° C. for 5 hr. Extractivework-up with EA gave a mixture of title compounds (500 mg, ˜70:30 byLCMS) which were carried on without purification. LCMS: 328.1 (M+1)⁺.

Step 3: 6-methyl-2-(1-methylpyrazol-4-yl)pyrido[4,3-d]pyrimidin-5-one

The mixture of title compounds from step 2 (500 mg) was treated withethanolic methylamine (15 mL, 30% CH₃NH₂ in EtOH) and heated at 80° C.for 5 hr. After concentration, the resulting solids were triturated withhexane (10 mL) and collected to give the title compound (220 mg, 55.0%).¹H NMR (CDCl₃, 400 MHz): δ 9.57 (s, 1H), 8.27 (s, 1H), 8.21 (s, 1H),7.46 (d, J=7.6 Hz, 1H), 6.59 (d, J=7.6 Hz, 1H), 4.00 (s, 3H), 3.61 (s,3H). LCMS: 242.0 (M+1)⁺.

Step 4:8-bromo-6-methyl-2-(1-methylpyrazol-4-yl)pyrido[4,3-d]pyrimidin-5-one

The title compound from step 3 (220 mg, 0.912 mmol) and Br₂ (146 mg,0.912 mmol) in HOAc (15 mL) were stirred at room temp for 2 hr. H₂O (150mL) was added, and the resulting solid was collected and triturated withDCM: PE=10:1 (10 mL) to give the title compound (200 mg, yield: 69.0%).¹H NMR (CDCl₃, 400 MHz): δ 9.54 (s, 1H), 8.33 (s, 1H), 8.27 (s, 1H),7.77 (s, 1H), 4.01 (s, 3H), 3.62 (s, 3H).

Step 5:8-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-6-methyl-2-(1-methylpyrazol-4-yl)pyrido[4,3-d]pyrimidin-5-one

The title compound of step 4 (200 mg, 0.627 mmol), the title compound ofExample 90, step 1 (266 mg, 0.752 mmol), K₃PO₄ (400 mg, 1.881 mmol) andPd(dppf)Cl₂ (10 mg) in dioxane (4 mL) and H₂O (1 mL) were heated at 70°C. for 18 hr under N₂. After preparative HPLC, the title compound (104.5mg, 35.8%) was obtained as an off white solid. ¹H NMR (CDCl₃, 400 MHz):δ 9.64 (s, 1H), 8.24-8.18 (m, 2H), 8.07 (s, 1H), 7.96 (dd, J₁=8.8 Hz,J₂=2.4 Hz, 1H), 7.77 (s, 1H), 7.10 (d, J=8.8 Hz, 1H), 3.95 (s, 3H), 3.91(d, J=7.2 Hz, 2H), 3.68 (s, 3H), 3.12 (s, 3H), 1.13-1.01 (m, 1H),0.54-0.44 (m, 2H), 0.21-0.14 (m, 1H). LCMS: 466.1 (M+1)⁺.

Example 225:8-(5-ethylsulfonyl-2-propoxyphenyl)-6-methyl-2-(1-methylpyrazol-4-yl)pyrido[4,3-d]pyrimidin-5-oneStep 1: 2-bromo-4-ethylsulfonyl-1-propoxybenzene

To a soln of n-propanol (224 mg, 3.74 mmol) in THF (10 mL) was added NaH(112 mg, 2.80 mmol, 60% in mineral oil) at 0° C. After stirring at 0° C.for 30 min, 2-bromo-4-(ethanesulfonyl)-1-fluorobenzene (500 mg, 1.87mmol) was added and the mixture was stirred at room temp for 4 hr.Addition of satd NH₄Cl (10 mL) followed by EA extractive work-up gavethe title compound (300 mg, yield: 52.3%) which was carried on directly.

Step 2:2-(5-ethylsulfonyl-2-propoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

The title compound of step 1 (300 mg, 0.98 mmol),4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(622 mg, 2.45 mmol), KOAc (288 mg, 2.94 mmol), Pd₂(dba)₃ (92 mg, 0.10mmol), and X-Phos (62 mg, 0.13 mmol) in dioxane (5 mL) were purged withAr and heated at 70° C. for 12 hr. CH₂Cl₂ extractive work-up and silicagel chromatography (PE:EA=20:1˜5:1) gave the title compound (200 mg,yield: 57.7%) as a grey solid. ¹H NMR (CDCl₃, 400 MHz): δ 8.13 (s, 1H),7.91 (d, J=8.8 Hz, 1H), 6.95 (d, J=8.8 Hz, 1H), 4.02 (t, J=5.6 Hz, 2H),3.13 (q, J=7.2 Hz, 2H), 1.89 (q, J=6.8 Hz, 2H), 1.36-1.25 (m, 15H), 1.12(t, J=6.8 Hz, 3H). LCMS: 272.9 (M+1)⁺.

Step 3:8-(5-ethylsulfonyl-2-propoxyphenyl)-6-methyl-2-(1-methylpyrazol-4-yl)pyrido[4,3-d]pyrimidin-5-one

The title compound of step 2 (60 mg, 0.17 mmol), the title compound ofExample 224, step 4 (64 mg, 0.20 mmol), K₃PO₄ (108 mg, 0.51 mmol), andPd(dppf)Cl₂ (15 mg, 0.02 mmol) in dioxane (8 mL) were purged with N₂ andheated at 70° C. for 18 hr. CH₂Cl₂ extractive work-up and preparativeHPLC gave the title compound (66.11 mg, yield: 83.3%) as a grey solid.¹H NMR (CDCl₃, 400 MHz): δ 9.64 (s, 1H), 8.19 (s, 1H), 8.12 (d, J=2.4Hz, 1H), 8.06 (s, 1H), 7.96 (dd, J₁=8.8 Hz, J₂=2.4 Hz, 1H), 7.70 (s,1H), 7.15 (d, J=8.4 Hz, 1H), 4.03-3.95 (m, 5H), 3.67 (s, 3H), 3.20 (q,J=7.2 Hz, 2H), 1.67-1.60 (m, 2H), 1.36 (t, J=7.2 Hz, 3H), 0.81 (t, J=7.2Hz, 3H). LCMS: 468.2 (M+1)⁺.

Example 226:8-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-6-methyl-2-(1-methylpyrazol-4-yl)pyrido[4,3-d]pyrimidin-5-one

The title compound was prepared in three steps in a similar manner asExample 225 except that cyclopropylmethanol was substituted forn-propanol in step 1. ¹H NMR (CDCl₃, 400 MHz): δ 9.64 (s, 1H), 8.22 (s,1H), 8.17 (d, J=2.0 Hz, 1H), 8.07 (s, 1H), 7.92 (dd, J₁=8.4 Hz, J₂=2.0Hz, 1H), 7.77 (s, 1H), 7.10 (d, J=8.4 Hz, 1H), 3.96 (s, 3H), 3.90 (d,J=6.8 Hz, 2H), 3.68 (s, 3H), 3.17 (q, J=7.2 Hz, 2H), 1.33 (t, J=7.2 Hz,3H), 1.08-1.06 (m, 1H), 0.52-0.47 (m, 2H), 0.21-0.17 (m, 2H). LCMS:480.2 (M+H)⁺.

Example 227:8-(2-ethoxy-5-ethylsulfonylphenyl)-6-methyl-2-(1-methylpyrazol-4-yl)pyrido[4,3-d]pyrimidin-5-one

The title compound was prepared in three steps in a similar manner asExample 225 except that ethanol was substituted for n-propanol instep 1. ¹H NMR (CDCl₃, 400 MHz): δ 9.64 (s, 1H), 8.19 (s, 1H), 8.10 (s,1H), 8.06 (s, 1H), 7.94 (d, J=8.8 Hz, 1H), 7.69 (s, 1H), 7.13 (d, J=8.8Hz, 1H), 4.13 (q, J=6.8 Hz, 2H), 3.95 (s, 3H), 3.67 (s, 3H), 3.17 (q,J=7.2 Hz, 2H), 1.34 (t, J=7.2 Hz, 3H), 0.81 (t, J=6.8 Hz, 3H). LCMS:454.1 (M+H)⁺.

Example 228:8-(2-ethoxy-5-ethylsulfonylphenyl)-6-methyl-2-(1-methylpyrazol-4-yl)pyrido[4,3-d]pyrimidin-5-one

2-bromo-4-methylsulfonyl-1-propoxybenzene was prepared in a similarmanner as Example 46, step 1 except that 1-chloropropane was substitutedfor (chloromethyl)cyclopropane and the resulting product was used toprepare4,4,5,5-tetramethyl-2-(5-methylsulfonyl-2-propoxyphenyl)-1,3,2-dioxaborolanein a manner similar to Example 225, step 2 which was then used toprepare the title compound in a manner similar as Example 225, step 3.¹H NMR (CDCl₃, 400 MHz): δ 9.64 (s, 1H), 8.19 (s, 1H), 8.16 (d, J=2.4Hz, 1H), 8.07 (s, 1H), 7.99 (dd, J₁=8.8 Hz, J₂=2.4 Hz, 1H), 7.70 (s,1H), 7.14 (d, J=8.8 Hz, 1H), 4.01 (t, J=6.4 Hz, 2H), 3.96 (s, 3H), 3.68(s, 3H), 3.12 (s, 3H), 1.67-1.61 (m, 2H), 0.78 (t, J=7.2 Hz, 3H). LCMS:454.1 (M+H)⁺.

Example 229:N-[4-(2,4-difluorophenoxy)-3-(1,5-dimethyl-6-oxopyridin-3-yl)phenyl]-N-methylmethanesulfonamide

The title compound of Example 102 (56 mg, 0.13 mmol) in DMF (0.2 mL) wastreated with NaH (60% dispersion in oil, 6 mg, 0.16 mmol). After about15 min, methyl iodide (0.012 mL, 0.2 mmol) was added. After completerxn, silica gel chromatography gave the title compound (55 mg, 0.13mmol) as a cream colored solid. ¹H NMR (400 MHz, DMSO-d₆): δ ppm1.96-2.17 (s, 3H) 2.98 (s, 3H) 3.25 (s, 3H) 3.49 (s, 3H) 6.82 (d, J=8.84Hz, 1H) 7.21-7.40 (m, 3H) 7.40-7.54 (m, 2H) 7.59 (s, 1H) 7.82 (d, J=2.53Hz, 1H). LCMS (M+H)⁺: 435.

Example 230:N-[4-(2,4-difluorophenoxy)-3-(1,5-dimethyl-6-oxopyridin-3-yl)phenyl]-N-(oxetan-3-yl)methanesulfonamide

The title compound of Example 102 (46 mg, 0.11 mmol), Cs₂CO₃ (150 mg,0.46 mmol), KI (10 mg, 0.06 mmol) and oxetan-3-yl4-methylbenzenesulfonate (30 mg, 0.13 mmol) in DMF (0.9 mL) weremicrowaved at 130° C. for 2 hr. Additional oxetan-3-yl4-methylbenzenesulfonate (65 mg, 0.29 mmol) and Cs2CO3 (126 mg, 0.39mmol) were added and microwave resumed at 130° C. for 2 hr more. Themixture was purified by silica gel chromatography (EA) to give the titlecompound (20 mg, 0.04 mmol) as cream solids in 38% yield. ¹H NMR (400MHz, DMSO-d₆): δ ppm 2.03 (s, 3H) 2.98 (s, 3H) 3.50 (s, 3H) 4.41 (t,J=6.82 Hz, 2H) 4.58 (t, J=6.95 Hz, 2H) 5.30 (quin, J=7.01 Hz, 1H) 6.83(d, J=8.84 Hz, 1H) 7.06-7.20 (m, 1H) 7.22-7.35 (m, 2H) 7.39 (d, J=2.53Hz, 1H) 7.43-7.57 (m, 1H) 7.60 (s, 1H) 7.83 (d, J=2.27 Hz, 1H). LCMS(M+H)⁺: 477.

Example 231:8-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-6-methylpyrido[4,3-d]pyrimidin-5-oneStep 1: 6H-pyrido[4,3-d]pyrimidin-5-one

Under N₂, ethyl 3-oxobutanoate (40.12 g, 0.31 mol) and 1,3,5-triazine(25.00 g, 0.31 mol) in dry EtOH (90 mL) were heated at 80° C. for 2 hrand EtONa (8.39 g, 0.12 mol) was added and heating continued at 80° C.for 18 hr. The mixture was concentrated and H₂O (300 mL) was added.Acidification with concentrated HCl (50 mL) resulted in a precipitatewhich was collected and washed with cold acetone (20 mL) and dried undervacuum to give the title compound (1.20 g, yield: 2.6%) as a brownsolid. ¹H NMR (DMSO-d₆, 400 MHz): δ 11.92 (brs, 1H), 9.41 (s, 1H), 9.32(s, 1H), 7.72 (dd, J₁=7.6 Hz, J₂=6.4 Hz, 1H), 6.57 (d, J=7.6 Hz, 1H).

Step 2: 8-bromo-6H-pyrido[4,3-d]pyrimidin-5-one

To the title compound of step 1 (200 mg, 1.36 mmol) in DMF (20 mL) wasadded NBS (242 mg, 1.36 mmol) at 0° C. The resulting mixture was stirredat 15° C. for 2 hr, and then concentrated and treated with acetone (20mL). The resulting solid was collected to give the title compound (220mg, yield: 71.6%) as a yellow solid. ¹H NMR (DMSO-d₆, 400 MHz): δ 12.25(brs, 1H), 9.46 (s, 1H), 9.42 (s, 1H), 8.12 (d, J=6.0 Hz, 1H).

Step 3: 8-bromo-6-methylpyrido[4,3-d]pyrimidin-5-one

Sodium hydride (21 mg, 0.53 mmol, 60% in mineral oil) was added to thetitle compound of step 2 (100 mg, 0.44 mmol) in DMF (10 mL) at 0° C.After stirring 0.5 hr, MeI (126 mg, 0.88 mmol) was added and stirringcontinued at 0° C. for 2 hr. Following extractive work-up with EA, thetitle compound (80 mg, yield: 75.3%) was obtained as a yellow solid. ¹HNMR (DMSO-d6, 400 MHz): δ 9.47 (s, 1H), 9.46 (s, 1H), 8.53 (s, 1H), 3.54(s, 3H). LCMS: 240.0; 242.0 (M+H)⁺.

Step 4:8-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-6-methylpyrido[4,3-d]pyrimidin-5-one

The title compound of step 3 (100 mg, 0.42 mmol), the title compound ofExample 90, step 1 (147 mg, 0.42 mmol), Pd(dppf)Cl₂ (62 mg, 0.08 mmol),K₃PO₄ (221 mg, 1.04 mmol) in dioxane (4 mL) and H₂O (0.5 mL) was purgedwith N₂ and heated at 100° C. for 18 hr. Following CH₂Cl₂ extractivework-up, silica gel chromatography (PE:EA=2:1˜0:1) and preparative HPLC,the title compound (54.57 mg, yield: 34.2%) was obtained as a yellowsolid. ¹H NMR (DMSO-d₆, 400 MHz): δ 9.54 (s, 1H), 9.30 (s, 1H), 8.18 (s,1H), 7.93 (dd, J₁=8.8 Hz, J₂=2.4 Hz, 1H), 7.85 (d, J=2.4 Hz, 1H), 7.31(d, J=8.8 Hz, 1H), 3.91 (d, J=6.8 Hz, 2H), 3.61 (s, 3H), 3.20 (s, 3H),0.94-0.92 (m, 1H), 0.35-0.30 (m, 2H), 0.10-0.06 (m, 2H). LCMS: 386.0(M+H)⁺.

Example 232:8-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-6-methylpyrido[4,3-d]pyrimidin-5-one

2-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolaneas prepared in Example 226 was reacted with the title compound of 231,step 3 in a manner similar to 231, step 4 to give the title compound. ¹HNMR (DMSO-d₆, 400 MHz): δ 9.54 (s, 1H), 9.30 (s, 1H), 8.17 (s, 1H), 7.88(dd, J₁=8.8 Hz, J₂=2.4 Hz, 1H), 7.80 (d, J=2.4 Hz, 1H), 7.31 (d, J=8.8Hz, 1H), 3.92 (d, J=6.8 Hz, 2H), 3.61 (s, 3H), 3.27 (q, J=7.2 Hz, 2H),1.14 (t, J=7.2 Hz, 3H), 0.94-0.93 (m, 1H), 0.34-0.32 (m, 2H), 0.10-0.08(m, 2H). LCMS: 400.0 (M+H)⁺.

Example 233:8-[2-(2,4-difluorophenoxy)-5-methylsulfonylphenyl]-6-methylpyrido[4,3-d]pyrimidin-5-oneStep 1:8-(2-fluoro-5-methylsulfonylphenyl)-6-methylpyrido[4,3-d]pyrimidin-5-one

2-bromo-1-fluoro-4-methylsulfonylbenzene was substituted for the titlecompound of Example 225, step 1 and was converted to2-(2-fluoro-5-methylsulfonylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolanein a manner similar to Example 225, step 2 and then reacted with thetitle compound of Example 231, step 3 in a manner similar to Example231, step 4. LCMS: 333.9 (M+H)⁺.

Step 2:8-[2-(2,4-difluorophenoxy)-5-methylsulfonylphenyl]-6-methylpyrido[4,3-d]pyrimidin-5-one

The title compound of step 2 (60 mg, crude), 2,4-difluorophenol (35 mg,0.27 mmol) and Cs₂CO₃ (176 mg, 0.54 mmol) in DMSO (2 mL) was heated at100° C. for 12 hr. EA extractive work-up and preparative HPLC gave thetitle compound (10.04 mg, yield: 13.6% for two steps) as a yellow solid.¹H NMR (CDCl₃, 400 MHz): δ 9.73 (s, 1H), 9.34 (s, 1H), 8.02 (d, J=2.4Hz, 1H), 7.92 (dd, J₁=8.8 Hz, J₂=2.4 Hz, 1H), 7.72 (s, 1H), 7.19-7.17(m, 1H), 6.97-6.89 (m, 3H), 3.72 (s, 3H), 3.12 (s, 3H). LCMS: 444.1(M+H)⁺.

Example 234:8-[2-(2,4-difluorophenoxy)-5-ethylsulfonylphenyl]-6-methylpyrido[4,3-d]pyrimidin-5-oneStep 1: 1-(2-bromo-4-ethylsulfonylphenoxy)-2,4-difluorobenzene

2-bromo-1-fluoro-4-ethylsulfonylbenzene (130 mg, 0.49 mmol),2,4-difluorophenol (78 mg, 0.60 mmol) and Cs₂CO₃ (478 mg, 1.47 mmol) inDMSO (5 mL) were heated at 100° C. for 12 hr. EA extractive work-up gavethe title compound (150 mg, yield: 80.5%) as a grey solid. ¹H NMR(CDCl₃, 400 MHz): δ 8.18 (d, J=2.0 Hz, 1H), δ 7.75 (dd, J₁=8.4 Hz,J₂=1.6 Hz, 1H), 7.22-7.16 (m, 1H), 7.06-6.95 (m, 2H), 6.80 (d, J=8.8 Hz,1H), 3.16 (q, J=7.2 Hz, 2H), 1.33 (t, J=7.6 Hz, 3H). LCMS: 395.8(M+NH₄)⁺.

Step 2:2-[2-(2,4-difluorophenoxy)-5-ethylsulfonylphenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

The title compound of step 1 was substituted for the title compound ofExample 225, step 1 and reacted in a similar manner as Example 225, step2. ¹H NMR (CDCl₃, 400 MHz): δ 8.11 (d, J=2.8 Hz, 1H), δ 7.95 (dd, J₁=8.8Hz, J₂=2.4 Hz, 1H), 7.55-7.50 (m, 1H), 7.29-7.23 (m, 1H), 7.16-7.12 (m,1H), 6.99 (d, J=8.8 Hz, 1H), 3.32 (q, J=7.2 Hz, 2H), 1.26 (s, 12H), 1.12(t, J=7.2 Hz, 3H). LCMS: 342.8 (M+H) (free boronic acid)⁺.

Step 3:8-[2-(2,4-difluorophenoxy)-5-ethylsulfonylphenyl]-6-methylpyrido[4,3-d]pyrimidin-5-one

The title compound of step 2 was substituted for the title compound ofExample 225, step 2 and the title compound of Example 231, step 3 wassubstituted for the title compound of Example 224, step 4 and reacted ina similar manner as Example 225, step 3. ¹H NMR (CDCl₃, 400 MHz): δ 9.60(s, 1H), 9.27 (s, 1H), 8.12 (s, 1H), 8.02 (d, J=2.0 Hz, 1H), 7.94 (dd,J₁=8.8 Hz, J₂=2.0 Hz, 1H), 7.32-7.25 (m, 1H), 7.15-7.09 (m, 1H),7.03-6.97 (m, 2H), 3.70 (s, 3H), 3.27 (q, J=7.6 Hz, 2H), 1.30 (t, J=7.2Hz, 3H). LCMS: 458.0 (M+H)⁺.

Example 235:5-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-7-methyl-[1,2,4]triazolo[4,3-a]pyrazin-8-oneStep 1: 5-bromo-7H-[1,2,4]triazolo[4,3-a]pyrazin-8-one

To a soln of 5-bromo-8-methoxy-[1,2,4]triazolo[4,3-a]pyrazine (BorchardtWO 2011/112766) (500 mg, 2.18 mmol) in HOAc (3 mL) was added HCl (1N,5.00 mL). The mixture was heated at 110° C. for 4 hr and concentrated togive the title compound (400 mg, yield: 85%) as a yellow solid which wascarried on without purification. ¹H NMR (DMSO-d6, 400 MHz): δ 11.78 (s,1H), 9.25 (s, 1H), 7.25 (d, J=6.0 Hz, 1H). LCMS: 214.9 (M+H)⁺.

Step 2: 5-bromo-7-methyl-[1,2,4]triazolo[4,3-a]pyrazin-8-one

To a soln of the title compound of step 1 (400 mg, 1.86 mmol) in DMF (4mL) was added NaH (149 mg, 3.72 mmol, 60% in mineral oil) in portions at0° C. under N₂. The mixture was stirred at 20° C. for 1 hr, and methyliodide (792 mg, 5.58 mmol) was added. After stirring at 20° C. for 5 hr,H₂O was added. Methylene chloride:2-propanol (10:1) extractive work-upgave the title compound (200 mg, yield: 47%) as a light yellow solidwhich was carried on without purification. ¹H NMR (DMSO-d6, 400 MHz): δ9.26 (s, 1H), 7.60 (s, 1H), 3.42 (s, 3H). LCMS: 228.9 (M+H)⁺.

Step 3:5-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-7-methyl-[1,2,4]triazolo[4,3-a]pyrazin-8-one

The title compound of step 2 (40 mg, 0.175 mmol), the title compound ofExample 90, step 1 (62 mg, 0.175 mmol), K₃PO₄ (93 mg, 0.438 mmol) andPd(dppf)Cl₂ (13 mg, 0.018 mmol) in dioxane (2 mL) and H₂O (1 mL) was N₂purged and microwaved at 70° C. for 2 hr. Silica gel chromatography(PE:EA=1:4) followed by preparative HPLC gave the title compound (31.89mg, yield: 48.6%) as an off-white solid. ¹H NMR (DMSO-d6, 400 MHz): δ8.91 (s, 1H), 8.06 (dd, J₁=8.8 Hz, J₂=2.4 Hz, 1H), 7.96 (d, J=2.4 Hz,1H), 7.43-7.04 (m, 2H), 4.04 (d, J=6.8 Hz, 2H), 3.52 (s, 3H), 3.23 (s,3H), 0.99-0.96 (m, 1H), 0.41-0.36 (m, 2H), 0.23-0.20 (m, 2H). LCMS:375.0 (M+H)⁺.

Example 236:N-[4-(2,4-difluorophenoxy)-3-(7-methyl-8-oxo-[1,2,4]triazolo[4,3-a]pyrazin-5-yl)phenyl]ethanesulfonamide

The title compound of Example 235, step 2 (40 mg, 0.175 mmol),N-[4-(2,4-difluoro-phenoxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethanesulfonamide(77 mg, 0.175 mmol), K₃PO₄ (93 mg, 0.438 mmol) and Pd(dppf)Cl₂ (13 mg,0.018 mmol) in dioxane (2 mL) and H₂O (1 mL) was N₂ purged andmicrowaved at 70° C. for 2 hr. Preparative HPLCgave the title compound(38.75 mg, yield: 49.3%) as an off-white solid. ¹H NMR (CDCl₃, 400 MHz):δ 8.60 (s, 1H), 7.64 (d, J=2.8 Hz, 1H), 7.45 (dd, J₁=8.8 Hz, J₂=2.8 Hz,1H), 7.10-7.05 (m, 1H), 6.99-6.88 (m, 3H), 6.74 (d, J=8.8 Hz, 1H), 3.67(s, 3H), 3.18 (q, J=7.2 Hz, 2H), 1.40 (t, J=7.2 Hz, 3H). LCMS: 462.0(M+H)⁺.

Example 237:7-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-5-methyl-[1,3]oxazolo[4,5-c]pyridin-4-oneStep 1: 3-nitro-4-hydroxy-1-methylpyridin-2-one

To 4-hydroxy-3-nitro-1H-pyridin-2-one (300 mg, 1.9 mmol) in DMF (5 mL)was added NaH (176 mg, 4.4 mmol, 60% in mineral oil) at 0° C. under N₂.After stirring at 0° C. for 30 min, CH₃I (272 mg, 1.9 mmol) in DMF (5mL) was added dropwise, and the mixture was stirred for 2 hr at 25° C.Satd aq NH₄Cl was added, the pH was adjusted to ˜3 with 1N HCl and EAextractive work-up gave a residue that was triturated with MeOH (0.5ml):EA (10 mL):PE (5 mL). After filtration, the trituratate wasevaporated to give the title compound (300 mg, 91%) as a yellow solid.¹H NMR (CDCl₃, 400 MHz): δ 7.75 (d, J=7.2 Hz, 1H), 6.17 (d, J=7.2 Hz,1H) 3.54 (s, 3H). LCMS: 171.0 (M+1)⁺.

Step 2: 1-methyl-3-nitro-4-phenylmethoxypyridin-2-one

To the title compound of step 1 (300 mg, 1.7 mmol) in CH₃CN (15 mL) wasadded K₂CO₃ (726 mg, 5.2 mmol) at 25° C. under N₂. After stirring for 30min, benzyl bromide (450 mg, 2.6 mmol) was added, and the mixture washeated at 50° C. for 20 hr. Following CH₂Cl₂ extractive work-up, theresidue was triturated with PE:EA (3:1) to give the title compound (250mg, 54%) as a yellow solid. ¹H NMR (CDCl₃, 400 MHz): δ 7.43-7.29 (m,6H), 6.12 (d, J=7.2 Hz, 1H), 5.27 (s, 2H), 3.57 (s, 3H). LCMS: 261.0(M+1)⁺.

Step 3: 3-amino-4-hydroxy-1-methylpyridin-2-one hydrochloride

To the title compound of step 2 (2.00 g, 7.69 mmol, 1.00 Eq) in MeOH (50mL)/EtOH (50 mL)/DMF (10 mL) was added Pd—C (10%, 0.2 g) under N₂. Thesuspension was purged with H₂ three times and hydrogenated under aballoon for 5 h. The catalyst was removed by filtration, and anhydrousHCl in methanol (10 mL, 1.25 M) was added. Concentration left a residuewhich was treated a second time with HCl in methanol. Evaporation of thevolatile components and trituration with DCM (30 mL)/hexane (30 mL) gavethe title compound (1.29 g, 7.30 mmol, yield: 95%) as a pink HCl saltafter drying. ¹H NMR (DMSO-d6, 400 MHz): δ 9.45-8.02 (br, 3H), 7.64 (d,J=7.6 Hz, 1H), 3.27 (d, J=7.6 Hz, 1H), 3.43 (s, 3H). LCMS: 163.0(M+Na)⁺.

Step 4: 5-methyl-[1,3]oxazolo[4,5-c]pyridin-4-one

The title compound of step 3 (500 mg, 2.8 mmol) in triethyl orthoformate(10 mL) was refluxed for 5 hr. The mixture was concentrated in vacuo at55° C. and purified by silica gel chromatography (PE:EA=1:1) to give thetitle compound (130 mg, yield: 30%) as a yellow solid. ¹H NMR (CDCl₃,400 MHz): δ 7.99 (s, 1H), 7.36 (d, J=8.0 Hz, 1H), 6.60 (d, J=8.0 Hz,1H), 3.69 (s, 3H).

Step 5: 7-bromo-5-methyl-[1,3]oxazolo[4,5-c]pyridin-4-one

To the title compound of step 4 (100 mg, 0.7 mmol) in CH₃CN (5 mL) wasadded NBS (154 mg, 0.8 mmol) at 20° C. After 2 hr, the mixture wasconcentrated in vacuum at 45° C. Purification by silica gelchromatography (PE:EA=5:1˜2:1) to gave the title compound (70 mg, yield:45%) as a yellow solid. ¹H NMR (CDCl₃, 400 MHz): δ 8.04 (s, 1H), 7.52(s, 1H), 3.69 (s, 3H).

Step 6:7-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-5-methyl-[1,3]oxazolo[4,5-c]pyridin-4-one

The title compound of step 5 (60 mg, 0.3 mmol) in dioxane (2 mL) and H₂O(0.4 mL) was stirred at 15° C. under N₂ for 30 min. Pd(dppf)Cl₂ (19 mg,0.026 mmol), the title compound of Example 90, step 1 (120 mg, 0.3 mmol)and K₃PO₄ (166 mg, 0.8 mmol,) were added at 15° C. under N₂. The rxnmixture was heated at 60° C. for 12 hr. Purification by silica gelchromatography (EA) and preparative HPLC gave the title compound (20.63mg, 20%) as a yellow solid. ¹H NMR (CDCl₃, 400 MHz): δ 8.03 (d, J=2.0Hz, 1H), 8.02 (s, 1H), 7.96 (dd, J₁=8.4 Hz, J₂=2.0 Hz, 1H), 7.09 (d,J=8.4 Hz, 1H), 3.96 (d, J=6.8 Hz, 2H), 3.76 (s, 3H), 3.1 (s, 3H), 1.18(m, 1H), 0.60 (m, 2H), 0.30 (m, 2H). LCMS: 375.1 (M+H)⁺.

Example 238:7-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2,5-dimethyl-[1,3]oxazolo[4,5-c]pyridin-4-one

The title compound was prepared from the title compound of Example 237,step 3 in a similar manner as Example 237, steps 4-6 except thattriethyl orthoacetate was substituted for triethyl orthoformate. ¹H NMR(400 MHz, DMSO-d₆): δ ppm 0.25 (q, J=4.72 Hz, 2H) 0.48 (q, J=5.89 Hz,2H) 1.11 (m, 1H) 2.54 (s, 3H) 3.21 (s, 3H) 3.60 (s, 3H) 4.00 (d, J=6.82Hz, 2H) 7.34 (d, J=8.59 Hz, 1H) 7.88-7.98 (m, 3H). LCMS: 389 (M+H)⁺.

Example 239:5-methyl-7-[5-(methylsulfonylmethyl)-2-(2,2,2-trifluoroethoxy)phenyl]-[1,3]oxazolo[4,5-c]pyridin-4-one

The title compound of Example 237, step 5 and the title compound ofExample 370, step 1 were reacted in a manner similar to Example 237,step 6 to give the title compound. ¹H NMR (CDCl₃, 400 MHz): δ 8.00 (s,1H), 7.62 (s, 1H), 7.60 (s, 1H), 7.47 (d, J=8.4 Hz, 1H), 7.02 (d, J=8.4Hz, 1H), 4.42 (q, J=8.0 Hz, 2H), 4.28 (s, 2H), 3.74 (s, 3H), 2.87 (s,3H). LCMS: 417.0 (M+H)⁺.

Example 240:N-[4-(2,4-difluorophenoxy)-3-(5-methyl-4-oxo-[1,3]oxazolo[4,5-c]pyridin-7-yl)phenyl]ethanesulfonamide

N-[4-(2,4-difluorophenoxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethanesulfonamidewas prepared from the title compound of Example 122, step 1 and4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolanein a manner similar to Example 208, step 5 and reacted with the titlecompound of Example 237, step 5 in a manner similar to Example 237, step6. ¹H NMR (CDCl₃, 400 MHz): δ 8.01 (s, 1H), 7.31 (d, J=8.4 Hz, 1H), 7.67(s, 1H), 7.48 (d, J=2.4 Hz, 1H), 7.22 (dd, J₁=8.8 Hz, J₂=2.4 Hz, 1H),7.18 (m, 1H), 7.03 (m, 1H), 6.84 (m, 2H), 3.74 (s, 3H), 3.17 (q, J=7.2Hz, 2H), 1.43 (t, J=7.2 Hz, 3H). LCMS: 462.1 (M+H)⁺.

Example 241:N-[4-(2,4-difluorophenoxy)-3-(2,5-dimethyl-4-oxo-[1,3]oxazolo[4,5-c]pyridin-7-yl)phenyl]ethanesulfonamide

7-bromo-2,5-dimethyl-[1,3]oxazolo[4,5-c]pyridin-4-one prepared inExample 238 andN-[4-(2,4-difluorophenoxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethanesulfonamideprepared in Example 240 were reacted in a manner similar to Example 237,step 6 to give the title compound. ¹H NMR (400 MHz, DMSO-d₆): δ ppm 1.23(t, J=6.95 Hz, 3H) 2.45 (s, 3H) 3.13 (d, J=7.83 Hz, 2H) 3.58 (s, 3H)6.95 (d, J=8.59 Hz, 1H) 7.03-7.30 (m, 3H) 7.30-7.48 (m, 2H) 7.91 (s, 1H)9.86 (s, 1H). LCMS: 476 (M+H)⁺.

Example 242:5-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-1-(cyclopropylmethyl)-3-methylpyridin-2-oneStep 1:5-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-3-methyl-1H-pyridin-2-one

5-bromo-3-methyl-1H-pyridin-2-one (950 mg, 5.05 mmol), the titlecompound of Example 90, step 1 (2.93 g, 5.95 mmol), Pd(dppf)Cl₂ (365 mg,0.5 mmol) and K₃PO₄ (2.14 g, 10.1 mmol) in dioxane (30 mL) and H₂O (5mL) was purged with N₂ and heated at 70° C. for 12 hr. Silica gelchromatography (PE:DCM:EA=3:0:1-0:1:3) gave impure title compound (990mg) as a yellow solid which was used directly in the next step. ¹H NMR(CDCl₃, 400 MHz): δ 12.57 (brs, 1H), 7.84 (d, J=8.8 Hz, 1H), 7.82 (s,1H), 7.65 (s, 1H), 7.03 (d, J=8.8 Hz, 1H), 3.96 (d, J=7.2 Hz, 1H), 3.07(s, 3H), 2.24 (s, 3H), 1.40-1.25 (m, 1H), 0.67-0.65 (m, 2H), 0.37-0.36(m, 2H). LCMS: 334.1 (M+1)⁺

Step 2:5-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-1-(cyclopropylmethyl)-3-methylpyridin-2-one

The title compound of step 1 (80 mg), K₂CO₃ (77 mg, 0.56 mmol)bromomethylcyclopropane (62 mg, 0.46 mmol) in DMF (2 mL) were heated at70° C. for 4 hr. EA extractive work-up and preparative HPLC gave thetitle compound (17 mg) as a yellow solid. ¹H NMR (CDCl₃, 400 MHz): δ7.85-7.83 (m, 2H), 7.67 (d, J=2.0 Hz, 1H), 7.53 (s, 1H), 7.03 (d, J=9.2Hz, 1H), 3.95 (d, J=6.8 Hz, 1H), 3.89 (d, J=7.2 Hz, 1H), 3.07 (s, 3H),2.23 (s, 3H), 1.34-1.26 (m, 2H), 0.68-0.65 (m, 2H), 0.65-0.61 (m, 2H),0.44-0.43 (m, 2H), 0.38-0.37 (m, 2H). LCMS: 388.2 (M+1)⁺.

Example 243:5-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-3-methyl-1-(2-methylpropyl)pyridin-2-one

The title compound from Example 242, step 1 was reacted in a mannersimilar to Example 242, step 2 except that 1-bromo-2-methylpropane wassubstituted for bromomethylcyclopropane to give the title compound. ¹HNMR (CDCl₃, 400 MHz); δ 7.85-7.82 (m, 2H), 7.56 (s, 1H), 7.53 (s, 1H),7.03 (d, J=8.4 Hz, 1H), 3.94 (d, J=7.2 Hz, 1H), 3.83 (d, J=7.2 Hz, 1H),3.07 (s, 3H), 2.30-2.26 (m, 1H), 2.23 (s, 3H), 1.28-1.27 (m, 1H), 1.00(s, 3H), 0.98 (s, 3H), 0.69-0.65 (m, 2H), 0.38-0.35 (m, 2H). LCMS: 390.2(M+1)⁺.

Example 244:5-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-1-(2-methoxyethyl)-3-methylpyridin-2-one

The title compound from Example 242, step 1 was reacted in a mannersimilar to Example 242, step 2 except that 1-bromo-2-methoxyethane wassubstituted for bromomethylcyclopropane to give the title compound. ¹HNMR (CDCl₃, 400 MHz): δ 7.86-7.83 (m, 2H), 7.65 (d, J=1.6 Hz, 1H), 7.59(s, 1H), 7.03 (d, J=8.4 Hz, 1H), 4.22 (t, J=4.8 Hz, 1H), 3.96 (d, J=6.8Hz, 1H), 3.74 (t, J=4.8 Hz, 1H), 3.34 (s, 3H), 3.07 (s, 3H), 2.23 (s,3H), 1.30-1.27 (m, 1H), 0.70-0.66 (m, 2H), 0.40-0.36 (m, 2H). LCMS:392.2 (M+1)⁺.

Example 245:5-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-3-methyl-1-(oxetan-3-ylmethyl)pyridin-2-one

Sodium hydride (42 mg, 1.04 mmol, 60% in mineral oil) was added to thetitle compound from Example 242, step 1 (80 mg) in anhydrous DMF (4 mL)After stirring 1 hr, oxetan-3-ylmethyl methanesulfonate (173 mg, 1.04mmol) was added and stirring continued for 18 hr. EA extractive work-upfrom 1 M HCl and preparative HPLC purification gave the title compound(24.0 mg) as an off-white solid. ¹H NMR (CDCl₃, 400 MHz): δ 7.85 (d,J=8.8 Hz, 1H), 7.82 (s, 1H), 7.62 (s, 1H), 7.51 (s, 1H), 7.03 (d, J=8.8Hz, 1H), 4.83 (t, J=7.2 Hz, 1H), 4.57 (t, J=6.4 Hz, 1H), 4.30 (d, J=7.2Hz, 1H), 3.95 (d, J=6.8 Hz, 1H), 3.62-3.56 (m, 1H), 3.07 (s, 3H), 2.21(s, 3H), 1.32-1.27 (m, 1H), 0.72-0.68 (m, 2H), 0.40-0.36 (m, 2H). LCMS:404.1 (M+1)⁺.

Example 246:5-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-3-methyl-1-(1,3-oxazol-4-ylmethyl)pyridin-2-one

The title compound from Example 242, step 1 was reacted in a mannersimilar to Example 245 except that 1,3-oxazol-4-ylmethylmethanesulfonate was substituted for oxetan-3-ylmethyl methanesulfonateto give the title compound. ¹H NMR (CDCl₃, 400 MHz): δ 7.82 (s, 5H),7.52 (s, 1H), 7.01 (d, J=9.2 Hz, 1H), 5.11 (s, 2H), 3.94 (d, J=6.8 Hz,1H), 3.06 (s, 3H), 2.21 (s, 3H), 1.27-1.24 (m, 1H), 0.68-0.65 (m, 2H),0.37-0.36 (m, 2H). LCMS: 415.1 (M+1)⁺.

Example 247:N-[3-[1-(cyclopropylmethyl)-5-methyl-6-oxopyridin-3-yl]-4-(2,4-difluoro-phenoxy)phenyl]ethanesulfonamide

5-bromo-3-methyl-1H-pyridin-2-one was N-alkylated withbromomethylcyclopropane to give5-bromo-1-(cyclopropylmethyl)-3-methylpyridin-2-one.5-bromo-1-(cyclopropylmethyl)-3-methylpyridin-2-one (100 mg, 0.41 mmol),[2-(2,4-difluorophenoxy)-5-(ethylsulfonylamino)phenyl]boronic acid (217mg, 0.5 mol), K₃PO₄ (263 mg, 1.24 mmol) and Pd(dppf)Cl₂ (30 mg, 41.3μmol) in dioxane (8 mL)/H₂O (1 mL) were purged with N₂ and heated at70-80° C. for 12 hr. Preparative HPLC gave the title compound (56.0 mg,28.6% yield) as dull-red semisolid. ¹H NMR (CDCl₃, 400 MHz): δ 7.74 (s,1H), 7.61 (s, 1H), 7.28 (d, J=2.0 Hz, 1H), 7.10-7.15 (m, 1H), 6.92-7.00(m, 2H), 6.82-6.89 (m, 1H), 6.80 (d, J=8.8 Hz, 1H), 6.71 (br. s., 1H),3.93 (d, J=7.2 Hz, 3H), 3.12-3.21 (m, 2H), 2.24 (s, 3H), 1.42 (t, J=7.2Hz, 3H), 1.22-1.33 (m, 1H), 0.57-0.67 (m, 2H), 0.36-0.43 (m, 2H). LCMS:475.1 (M+1)⁺.

Example 248:N-[4-[1-(cyclopropylmethyl)-5-methyl-6-oxopyridin-3-yl]-5-(2,4-difluorophenoxy)pyrimidin-2-yl]methanesulfonamideStep 1: 5-bromo-1-(cyclopropylmethyl)-3-methylpyridin-2-one

Potassium carbonate (1.32 g, 9.57 mmol) was added to5-bromo-3-methyl-2-hydroxy-pyridine (600 mg, 3.19 mmol) andbromomethylcyclopropane (861 mg, 6.38 mmol) in DMF (6 mL). After heatingat 70° C. for 3 hr, EA extractive work-up and silca gel chromatography(PE:EA=30:1˜10:1), the title compound (510 mg, yield: 66.0%) wasobtained as a white solid. ¹H NMR (CDCl₃, 400 MHz): δ 7.39 (d, J=2.0 Hz,1H), 7.26 (d, J=2.0 Hz, 1H), 3.77 (d, J=6.8 Hz, 2), 2.15 (s, 3H),0.65-0.60 (m, 2H), 0.40-0.37 (m, 2H). LCMS: 242.1, 244.1 (M+H)⁺.

Step 2:1-(cyclopropylmethyl)-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one

The title compound of step 1 (480 mg, 1.98 mmol),4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(1.01 g, 3.96 mmol), KOAc (582 mg, 5.94 mmol) and Pd(dppf)Cl₂ (146 mg,0.20 mmol) in dioxane (9 mL) was purged with N₂ and heated to 70° C. for8 hr. After silca gel chromatography (PE:EA=30:1˜10:1) the titlecompound (415 mg, ˜70% purity on ¹H NMR, yield: 55.1%) was obtained aslight yellow oil. ¹H NMR (CDCl₃, 400 MHz): δ 7.69 (s, 1H), 7.49 (s, 1H),3.82 (d, J=6.8 Hz, 2H), 2.14 (s, 3H), 1.32 (s, 12H), 1.27-1.1.16 (m,1H), 0.61-0.56 (m, 2H), 0.42-0.39 (m, 2H). LCMS: 290.3 (M+H)⁺.

Step 3:1-(cyclopropylmethyl)-5-[5-(2,4-difluorophenoxy)-2-methylsulfonyl-pyrimidin-4-yl]-3-methylpyridin-2-one

The title compound of Example 149, step 3 (200 mg, 0.62 mmol), the titlecompound of step 2 (250 mg, 0.69 mmol, 70% purity), Pd(dppf)Cl₂ (88 mg,0.12 mmol) and K₃PO₄ (3M, 0.6 mL) in dioxane (6 mL) were purged with N₂and heated to 70° C. for 4 hr. After silica gel chromatography(PE:EA=3:1˜1:1) the title compound (220 mg, yield: 78.8%) was obtainedas a yellow solid. ¹H NMR (CDCl₃, 400 MHz): δ 7.45 (d, J=2.0 Hz, 1H),8.25 (s, 1H), 8.16 (s, 1H), 7.24-7.22 (m, 1H), 7.12-7.10 (m, 1H),7.10-7.03 (m, 1H), 3.92 (d, J=7.2 Hz, 2H), 3.38 (s, 3H), 2.26 (s, 3H),1.27-1.21 (m, 1H), 0.65-0.60 (m, 2H), 0.42-0.38 (m, 2H). LCMS: 448.1(M+H)⁺.

Step 4:N-[4-[1-(cyclopropylmethyl)-5-methyl-6-oxopyridin-3-yl]-5-(2,4-difluorophenoxy)pyrimidin-2-yl]methanesulfonamide

Methanesulfonamide (68 mg, 0.71 mmol), NaH (28 mg, 0.7 mmol, 60% inmineral oil) and the title compound from step 3 (80 mg, 0.18 mmol) inDMF (2 mL) were reacted in a similar manner as Example 152, step 6 togive the title compound (45.00 mg, yield: 54.4%) as an off-white solid.¹H NMR (CDCl₃, 400 MHz) δ 8.81 (s, 1H), 8.60 (d, J=2.0 Hz, 1H), 8.14 (s,1H), 8.12 (s, 1H), 7.05-6.98 (m, 2H), 6.91-6.89 (m, 1H), 3.87 (d, J=7.2Hz, 2H), 3.45 (s, 3H), 2.23 (s, 3H), 1.25-1.22 (m, 1H), 0.64-0.59 (m,2H), 0.40-0.37 (m, 2H). LCMS: 463.1 (M+H)⁺.

Example 249:N-[4-[1-(cyclopropylmethyl)-5-methyl-6-oxopyridin-3-yl]-5-(2,4-difluorophenoxy)pyrimidin-2-yl]ethanesulfonamide

The title compound of Example 248, step 3 was treated with EtSO₂NH₂instead of MeSO₂NH₂ in a manner similar to Example 248, step 4 to givethe title compound. ¹H NMR (CDCl₃, 400 MHz): δ 9.09 (s, 1H), 8.60 (s,1H), 8.16 (s, 1H), 8.11 (s, 1H), 7.04-6.96 (m, 2H), 6.91-6.89 (m, 1H),3.87 (d, J=7.2 Hz, 2H), 3.64 (q, J=7.2 Hz, 2H), 2.22 (s, 3H), 1.44 (t,J=7.2 Hz, 3H), 1.25-1.23 (m, 1H), 0.62-0.60 (m, 2H), 0.38-0.37 (m, 2H).LCMS: 477.2 (M+H)⁺.

Example 250:1-(cyclopropylmethyl)-5-[6-(2,4-difluorophenoxy)-3-(methylsulfonylmethyl)-4-oxocyclohexa-1,5-dien-1-yl]-3-methylpyridin-2-one

The title compound from Example 248, step 2 was reacted with the titlecompound of Example 381, step 4 in a manner similar to Example 248, step3 to give the title compound. ¹H NMR (CDCl₃, 400 MHz): δ 7.47 (s, 1H),7.41 (s, 1H), 7.37 (s, 1H), 7.18-7.16 (m, 1H), 7.04-7.02 (m, 1H),7.01-6.98 (m, 1H), 5.69 (s, 1H), 5.17 (s, 2H), 3.86 (d, J=7.2 Hz, 2H),2.99 (s, 3H), 2.20 (s, 3H), 1.28-1.27 (m, 1H), 0.65-0.60 (m, 2H),0.42-0.39 (m, 2H). LCMS: 477.1 (M+H)⁺.

Example 251:1-cyclopropyl-5-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-3-methylpyridin-2-oneStep 1: 5-bromo-1-cyclopropyl-3-methylpyridin-2-one

At room temp, NBS (63 mg, 0.35 mmol) was added to1-cyclopropyl-3-methylpyridin-2-one (Racine et al., Chem. Communications2013, 49(67) 7412-14) (53 mg, 0.36 mmol) in CH₃CN (0.7 mL). After 1 hr,EA extractive work-up from sat′d aq NaHCO₃ gave the title compound asyellow solids in quantitative yield.

Step 2:1-cyclopropyl-5-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-3-methylpyridin-2-one

The title compound of step 1 was reacted with2-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolanein a manner similar to Example 224, step 5. Silica gel chromatography(40-75% EA in hexane) gave the title compound (31 mg, 0.08 mmol, 42%) asa tan foam that turned to a glass upon standing. ¹H NMR (400 MHz,CDCl₃): δ ppm 0.36-0.42 (m, 2H) 0.60-0.75 (m, 2H) 0.81-1.02 (m, 1H,partially obscured) 1.05-1.37 (m, 7H, partially obscured) 2.22 (s, 3H)3.12 (q, J=7.41 Hz, 2H) 3.43 (br. s. 1H) 3.94 (d, J=6.82 Hz, 2H) 7.01(d, J=9.35 Hz, 1H) 7.45-7.53 (m, 1H) 7.62 (br. s., 1H) 7.72-7.83 (m,2H). LCMS: 388 (M+1)⁺.

Example 252:4-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-6-methylfuro[2,3-c]pyridine-7-oneStep 1: 4-bromo-6H-furo[2,3-c]pyridin-7-one

A mixture of 6H-furo[2,3-c]pyridin-7-one (1.0 g, 7.4 mmol) in DMF (30mL) was treated with NBS (1.32 g, 7.4 mmol) in three equal portions at0° C. After the resulting mixture was stirred at 15° C. for 2 hr, it wastreated with H₂O (100 mL) and extracted with EtOAc (30 mL×3). Thecombined organic layers were washed with brine (30 mL), dried overNa₂SO₄, filtered, and concentrated in vacuo. The residue was purified bychromatography on silica gel (PE:EtOAc=3:1) to give the title compound(600 mg, 38%) as a yellow solid. ¹H NMR (DMSO-d6, 400 MHz): δ 11.92 (s,1H), 8.23 (s, J=2.0 Hz, 1H), 7.47 (s, 1H), 6.88 (m, 1H), 6.88 (s, 1H).

Step 2: 4-bromo-6-methylfuro[2,3-c]pyridin-7-one

To a soln of the title compound of step 1 (500 mg, 2.3 mmol) stirred at0° C. in DMF (5 mL) was added NaH (68 mg, 2.81 mmol, 60% in mineraloil). After stirring at 0° C. for 30 min, methyl iodide (400 mg, 2.8mmol) was added dropwise. The icebath was removed, and mixture wasstirred at room temp for 4 hr. The rxn mixture was treated with satdNH₄Cl (aq 30 mL) and extracted with EtOAc (30 mL×2). The combinedorganic layers were washed with brine (30 mL), dried over Na₂SO₄,filtered, and concentrated in vacuo. The residue was purified bychromatography on silica gel (PE:EtOAc=10:1) to give the title compound(500 mg, 94%). ¹H NMR (CDCl₃, 400 MHz): δ 7.78 (d, J=2.0 Hz, 1H), 7.30(s, 1H), 6.70 (d, J=2.0 Hz, 1H), 3.66 (s, 3H). LCMS: (M+H)⁺229.

Step 3:4-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-6-methylfuro[2,3-c]pyridine-7-one

A mixture of the title compound of step 2 (150 mg, 0.66 mmol),2-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(336 mg, 1.0 mmol), NaHCO₃ (167 mg, 1.99 mmol), Pd(dppf)Cl₂ (35 mg,0.048 mmol) in dioxane/H₂O (10 mL/2.5 mL) was bubbled with Ar for 5 min.The sealed vial was stirred at 80° C. for 18 hr. The rxn mixture wasconcentrated, treated with DCM (30 mL), washed with H₂O (30 mL) andbrine (30 mL), dried over Na₂SO₄, filtered and concentrated in vacuo.The resulting residue was purified by prep-HPLC to give the titlecompound (63 mg, 25%) as a yellow solid. ¹H NMR (CDCl₃, 400 MHz): δ7.90-7.86 (m, 2H), 7.75 (d, J=1.6 Hz, 1H), 7.31 (s, 1H), 7.09 (d, J=8.4Hz, 1H), 6.57 (d, J=1.6 Hz, 1H), 3.95 (d, J=6.8 Hz, 2H), 3.74 (s, 3H),3.18-3.12 (q, J=7.6 Hz, 2H), 1.34 (t, J=7.6 Hz, 3H), 1.16-1.15 (m, 1H),0.61-0.55 (m, 2H), 0.31-0.27 (m, 2H). LCMS (M+H)⁺: 388.

Example 253:N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxofuro[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamide

The title compound was prepared in a manner similar to step 3 of Example252, by substitutingN-[4-(2,4-difluorophenoxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethanesulfonamidefor2-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.¹H NMR (CDCl₃, 400 MHz): δ 7.74 (s, 1H) 7.38 (m, 2H) 7.15 (m, 1H)6.93-9.92 (m, 2H) 6.82-6.76 (m, 3H) 6.44 (s, 1H) 3.72 (s, 3H) 3.19-3.16(q, J=7.2 Hz, 2H) 1.45 (t, J=7.2 Hz, 3H). LCMS (M+H)⁺: 461.

Example 254:4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-6-methylfuro[2,3-c]pyridine-7-one

A mixture of2-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(115 mg, 0.33 mmol), 4-bromo-6-methyl-6H,7H-furo[2,3-c]pyridin-7-one (75mg, 0.33 mmol), K₃PO₄ (175 mg, 0.83 mmol), Pd(dppf)Cl₂ (24 mg, 10%) indioxane/H₂O (2.2 mL/200 μL) was bubbled with N₂ for 5 min. The sealedvial was stirred at 70° C. for 90 min. The rxn mixture was filteredthrough a short plug of celite; the celite plug was washed with EtOAc(15 mL). The filtrate was washed with H₂O and brine. The organic layerwas dried over Na₂SO₄, filtered and concentrated in vacuo to afford abrown residue. The resulting residue was purified by prep-HPLC to affordthe title compound (60 mg, 49%) as a white solid. LCMS (M+H)⁺: 374.

Example 255:N-[4-(cyclopropylmethoxy)-3-(6-methyl-7-oxofuro[2,3-c]pyridine-4-yl)phenyl]ethanesulfonamideStep 1: 2-bromo-1-(cyclopropylmethoxy)-4-nitrobenzene

A 0.2 M soln of cyclopropyl methanol (441 μL, 5.5 mmol) in THF stirredat 0° C. under N₂ was treated with two equal portions of KOtBu (579 mg,5.2 mmol). After 5 min the icebath was removed; the mixture was stirredfor 30 min at room temp before resubmerging in the icebath and coolingto 0° C. A soln of 2-bromo-1-fluoro-4-nitro-benzene (1 g, 4.5 mmol) inTHF (3 mL) was added dropwise. After 20 min, the icebath was removed andthe mixture was stirred overnight. The rxn mixture was quenched with H₂O(50 mL) and extracted with EtOAc (3×50 ml). The combined organic layerswere washed brine (30 mL), dried over Na₂SO₄, filtered and concentratedin vacuo. The resulting residue was purified by silica gel CC using agradient of EtOAc (5 to 50%) in hexanes to afford the title compound(1.07 g, 88%) as a yellow solid.

Step 2: 3-bromo-4-(cyclopropylmethoxy)aniline

A mixture of 2-bromo-1-(cyclopropylmethoxy)-4-nitrobenzene (1.07 g, 3.9mmol), ammonium chloride (421 mg, 7.8 mmol), and iron powder (1.1 g, 20mmol) suspended in THF (6.5 mL), H₂O (2.5 mL) and EtOH (6.5 mL) washeated to 95° C. using microwave irradiation (normal) for 3 hr. Thecrude rxn mixture was filtered through a short plug of celite; thecelite plug was washed with MeOH (˜10 mL). The resulting filtrate wasconcentrated in vacuo. The resulting residue was diluted with EtOAc (50ml) and washed with satd bicarbonate soln (aq), dried over anhydrousmagnesium sulfate, filtered, and concentrated in vacuo to afford thetitle compound, (939 mg, 90%). The material was carried forward withoutany further purification. LCMS (M+H)⁺: 242.

Step 3: N-[3-bromo-4-(cyclopropylmethoxy)phenyl]ethane-1-sulfonamide

Ethylsulfonyl chloride (233 μL, 2.4 mmol) was added to a stirred soln of3-bromo-4-(cyclopropylmethoxy)aniline (520 mg, 2.2 mmol) and pyridine(520 μL, 6.5 mmol) in DCM (4 mL) at 0° C. under N₂. After the mixturewas allowed to warm to room temp and stirred for 12 hr, it was treatedwith 1N HCl (15 mL) and extracted with DCM (3×15 mL); the combinedorganic extracts were washed with satd bicarbonate soln (aq), dried overNa₂SO₄, filtered and concentrated in vacuo. The resulting residue waspurified by silica gel CC using a gradient of EtOAc (10 to 100%) inhexanes to afford the title compound (711 mg, 98%) as a yellow solid.LCMS (M+H)⁺: 335.

Step 4:N-[4-(cyclopropylmethoxy)-3-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethane-1-sulfonamide

A mixture ofN-[3-bromo-4-(cyclopropylmethoxy)phenyl]ethane-1-sulfonamide (711 mg,2.1 mmol),4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(1.1 g, 4.3 mmol), KOAc (470 mg, 4.8 mmol), Pd₂(dba)₃ (59 mg. 3%), and1,3,5,7-Tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane (62 mg,10%) was suspended in anhydrous dioxane (14 mL). The stirred mixture wascapped and purged with N₂ for 6 min using an oil bubbler as an outlet.After the N₂ inlet and outlet were removed, the capped flask was stirredat 70° C. for 3 hr. After cooling to ˜35° C., the rxn mixture wasfiltered through a short plug of celite; the celite plug was washed withEtOAc (75 mL). The filtrate was treated with H₂O and extracted withEtOAc; the combined organic layers were washed with brine, dried overNa₂SO₄, filtered and concentrated in vacuo to afford a tan residue. Theresidue was purified by silica gel CC using a gradient of EtOAc (5 to100%) in hexanes to afford the title compound (527 mg, 65%). LCMS(M+H)⁺: 382.

Step 5:N-[4-(cyclopropylmethoxy)-3-(6-methyl-7-oxofuro[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamide

A mixture ofN-[4-(cyclopropylmethoxy)-3-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethane-1-sulfonamide(138 mg, 0.38 mmol), 4-bromo-6-methyl-6H,7H-furo[2,3-c]pyridine-7-one(75 mg, 0.33 mmol), K₃PO₄ (175 mg, 0.83 mmol), Pd(dppf)Cl₂ (24 mg, 10%)in dioxane (2.2 mL) and H₂O (200 μL) was bubbled with N₂ for 5 min. Thesealed vial was stirred at 70° C. for 4 hr. After the rxn mixture wasfiltered through a short plug of celite, the celite plug was washed withEtOAc (15 mL). The filtrate was washed with H₂O and brine; the organiclayer was dried over Na₂SO₄, filtered and concentrated in vacuo toafford a tan residue. The resulting residue was purified by prep-HPLC toafford the title compound (21 mg, 16%) as a tan solid. ¹H NMR (400 MHz,DMSO-d₆): δ ppm 0.15-0.28 (m, 2H) 0.35-0.52 (m, 2H) 0.95-1.13 (m, 1H)1.14-1.26 (m, 3H) 2.98-3.09 (m, 2H) 3.57-3.65 (m, 3H) 3.77-3.87 (m, 2H)7.04-7.22 (m, 3H) 7.55-7.64 (m, 1H) 8.05-8.17 (m, 1H) 9.49-9.57 (m, 1H).LCMS (M+H)⁺: 403.

Example 256:N-[6-(2,4-difluorophenoxy)-5-(6-methyl-7-oxofuro[2,3-c]pyridin-4-yl)pyridine-3-yl]ethanesulfonamideStep 1: 3-bromo-2-(2,4-difluorophenoxy)-5-nitropyridine

A soln of 3-bromo-2-chloro-5-nitropyridine (2.4 g, 10 mmol) and2,4-difluorophenol (1 mL, 11 mmol) in NMP (20 ml) was treated withcesium carbonate (3.9 g, 12 mmol). The resulting mixture was heated to60° C. for 12 hr. The mixture was treated with H₂O (100 ml) andextracted with EtOAc (3×50 ml); the combined organic extracts werewashed with satd bicarbonate soln (aq), dried over Na₂SO₄, filtered andconcentrated in vacuo to afford a yellow solid. The solid was purifiedby silica gel CC (gradient of 5 to 30% EtOAc in hexanes) to afford thefree base of the title compound (2 g, 59%) as a yellow solid. LCMS(M+H)⁺: 332.

Step 2: 5-bromo-6-(2,4-difluorophenoxy)pyridin-3-amine

A mixture of 3-bromo-2-(2,4-difluorophenoxy)-5-nitropyridine (1.9 g, 5.9mmol), ammonium chloride (637 mg, 11.8 mmol), and iron powder (1.65 g,30 mmol) suspended in THF (10 mL), H₂O (3 mL), and EtOH (10 mL) washeated to 90° C. using microwave irradiation (normal) for 5 hr. Thecrude rxn mixture was filtered through a short plug of celite; thecelite plug was washed with warm (50° C.) MeOH (˜50 mL). The resultingfiltrate was concentrated in vacuo. The resulting residue was dilutedwith EtOAc (100 ml) and washed with satd bicarbonate soln (aq), driedover anhydrous magnesium sulfate, filtered, and concentrated in vacuo toafford the title compound, (824 mg, 46%). LCMS (M+H)⁺: 302.

Step 3:6-(2,4-difluorophenoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-3-amine

A mixture of 5-bromo-6-(2,4-difluorophenoxy)pyridin-3-amine (400 mg,1.33 mmol),4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(675 mg, 2.7 mmol), KOAc (325 mg, 3.3 mmol), Pd₂(dba)₃ (36 mg, 3%), and1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane (38 mg,10%) was suspended in dioxane (9 mL). The stirred rxn mixture was cappedand purged with N₂ for 5 to 7 min using an oil bubbler as an outlet.After the N₂ inlet and outlet were removed, the capped vial was stirredat 80° C. for 3 hr. After cooling to room temp, the rxn mixture wasfiltered through a short plug of celite; the celite plug was washed withEtOAc (50 mL). The filtrate was treated with H₂O and extracted withEtOAc; the combined organic layers were washed with brine, dried overNa₂SO₄, filtered and concentrated in vacuo to afford a tan residue. Theresidue was purified by silica gel CC using a gradient (20-70%) of EtOAcin hexanes to afford the title compound (163 mg, 35%). LCMS (M+H)⁺: 349.

Step 4:N-[6-(2,4-difluorophenoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-3-yl]ethanesulfonamide

Ethylsulfonyl chloride (50 μL, 52 mmol) was added to a stirred soln of6-(2,4-difluorophenoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-amine(163 mg, 0.5 mmol) and pyridine (113 μL) in DCM (2.4 mL) at 0° C. underN₂. After the mixture was allowed to warm to room temp and stir for 12hr, it was treated with H₂O (15 mL) and extracted with DCM (3×15 mL);the combined organic extracts were washed with satd bicarbonate soln(aq), dried over Na₂SO₄, filtered and concentrated in vacuo. Theresulting residue was purified by CC using a gradient of EtOAc (0 to100%) in DCM to afford the title compound (181 mg, 88%) as a tan solid.LCMS (M+H)⁺: 441.

Step 5:N-[6-(2,4-difluorophenoxy)-5-(6-methyl-7-oxofuro[2,3-c]pyridin-4-yl)pyridin-3-yl]ethanesulfonamide

A mixture ofN-[6-(2,4-difluorophenoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl]ethanesulfonamide(145 mg, 0.38 mmol), 4-bromo-6-methyl-6H,7H-furo[2,3-c]pyridin-7-one (75mg, 0.33 mmol), K₃PO₄ (175 mg, 0.83 mmol), Pd(dppf)Cl₂ (24 mg, 10%) indioxane/H₂O (2.2 mL/200 μL) was bubbled with N₂ for 5 min. The sealedvial was stirred at 70° C. for 4 hr. After the rxn mixture was filteredthrough a short plug of celite, the plug was washed with EtOAc (15 mL).The filtrate was washed with H₂O and brine, the organic layer was driedover Na₂SO₄, filtered and concentrated in vacuo to afford a tan residue.The resulting residue was purified by prep-HPLC to afford the titlecompound (50 mg, 33%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ ppm1.18-1.28 (m, 3H) 3.10-3.21 (m, 2H) 3.59-3.65 (m, 3H) 6.85-6.95 (m, 1H)7.07-7.19 (m, 1H) 7.35-7.51 (m, 2H) 7.73-7.79 (m, 1H) 7.80-7.85 (m, 1H)7.90-7.97 (m, 1H) 8.14-8.20 (m, 1H) 9.78-10.09 (m, 1H). LCMS (M+H)⁺:461.

Example 257:N-[6-(cyclopropylmethoxy)-5-(6-methyl-7-oxofuro[2,3-c]pyridin-4-yl)pyridine-3-yl]ethanesulfonamideStep 1: 3-bromo-2-(cyclopropylmethoxy)-5-nitropyridine

A soln of 3-bromo-2-chloro-5-nitropyridine (2.4 g, 10 mmol) andcyclopropylmethanol (970 μL, 12 mmol) in THF (50 ml) was treated withKOtBu (3.3 g, 15 mmol). After stirring at room temp for 12 hr, themixture was treated with H₂O (150 ml) and extracted with EtOAc (3×50ml); the combined organic extracts were washed with brine, dried overNa₂SO₄, filtered and concentrated in vacuo to afford a yellow solid. Thesolid was purified by CC using EtOAc (5% to 30%) in hexanes to affordthe title compound (1.3 g, 48%) as a yellow solid. LCMS (M+H)⁺: 274.

Step 2: 5-bromo-6-(cyclopropylmethoxy)pyridin-3-amine

A mixture of 3-bromo-2-(cyclopropylmethoxy)-5-nitropyridine (1 g, 3.7mmol), ammonium chloride (600 mg, 11.1 mmol), and iron powder (1.05 g,19 mmol) suspended in THF (6.2 mL), H₂O (2.3 mL) and EtOH (6.2 mL) washeated to 100° C. using microwave irradiation (normal) for 5 hr. Thecrude rxn mixture was filtered through a short plug of celite; thecelite plug was washed with warm (50° C.) MeOH (50 mL). The resultingfiltrate was concentrated in vacuo. The resulting residue was dilutedwith EtOAc (100 ml) and washed with satd bicarbonate soln (aq), driedover anhydrous magnesium sulfate, filtered, and concentrated in vacuo toafford the title compound, (539 mg, 60%). LCMS (M+H)⁺: 244.

Step 3: N-[5-bromo-6-(cyclopropylmethoxy)pyridin-3-yl]ethanesulfonamide

Ethylsulfonyl chloride (170 μL, 1.8 mmol) was added to a stirred soln of5-bromo-6-(cyclopropylmethoxy)pyridin-3-amine (440 mg, 1.8 mmol) andpyridine (725 μL) in DCM (4.5 mL) at 0° C. under N₂. After the mixturewas allowed to warm to room temp and stirred for 12 hr, it was treatedwith 1N HCl (15 mL) and extracted with DCM (3×15 mL); the combinedorganic extracts were washed with satd bicarbonate soln (aq), dried overNa₂SO₄, filtered and concentrated in vacuo. The resulting residue waspurified by silica gel CC using a gradient of EtOAc (0 to 100%) in DCMto afford the title compound (181 mg, 88%) as a tan solid. LCMS (M+H)⁺:336.

Step 4:N-[6-(cyclopropylmethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl]ethanesulfonamide

A mixture ofN-[5-bromo-6-(cyclopropylmethoxy)pyridin-3-yl]ethanesulfonamide (150 mg,0.45 mmol),4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(285 mg, 1.13 mmol), KOAc (132 mg, 1.35 mmol), and Pd(dppf)₂ (Cl)₂ (33mg, 10%) was suspended in anhydrous dioxane (5 mL). The stirred rxnmixture was capped and purged with N₂ for 5 min using an oil bubbler asan outlet. After the N₂ inlet and outlet were removed, the capped vialwas stirred at 70° C. for 3 hr. After cooling to room temp, the rxnmixture was filtered through a short plug of celite; the celite plug waswashed with EtOAc. The filtrate was treated with H₂O and separated;after the aq layer was washed with EtOAC (3×25 mL), the combined organiclayers were washed with brine, dried over Na₂SO₄, filtered andconcentrated in vacuo to afford a dark tan residue. The residue waspurified by silica gel CC using a gradient of 5 to 70% EtOAc in hexanesto afford the title compound (112 mg, 65%). LCMS (M+H)⁺: 383.

Step 5:N-[6-(cyclopropylmethoxy)-5-(6-methyl-7-oxofuro[2,3-c]pyridin-4-yl)pyridin-3-yl]ethanesulfonamide

A mixture ofN-[6-(cyclopropylmethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl]ethanesulfonamide(145 mg, 0.38 mmol), 4-bromo-6-methyl-6H,7H-furo[2,3-c]pyridin-7-one (25mg, 0.11 mmol), K₃PO₄ (58 mg, 0.28 mmol), Pd(dppf)Cl₂ (8 mg, 10%) indioxane/H₂O (1 mL/100 μL) was bubbled with N₂ for 5 min. The sealed vialwas stirred at 65° C. for 12 hr. The rxn mixture was filtered through ashort plug of celite; the celite plug was washed with EtOAc (15 mL). Thefiltrate was washed with H₂O and brine; the organic layer was dried overNa₂SO₄, filtered and concentrated in vacuo to afford a tan residue. Theresulting residue was purified by prep-HPLC to afford the title compound(21 mg, 48%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ ppm0.23-0.32 (m, 2H) 0.41-0.52 (m, 2H) 1.08-1.19 (m, 1H) 1.20-1.29 (m, 3H)3.05-3.16 (m, 2H) 3.58-3.63 (m, 3H) 3.64-3.66 (m, 1H) 4.08-4.17 (m, 2H)6.72-6.82 (m, 1H) 7.58-7.65 (m, 1H) 7.67-7.73 (m, 1H) 7.95-8.06 (m, 1H)8.10-8.18 (m, 1H) 9.41-9.86 (m, 1H). LCMS (M+H)⁺: 404.

Example 258:6-methyl-4-[5-(methylsulfonylmethyl)-2-(2,2,2-trifluoroethoxy)phenyl]furo[2,3-c]pyridin-7-oneStep 1:6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)furo[2,3-c]pyridin-7-one

A soln of 4-bromo-6-methylfuro[2,3-c]pyridin-7-one (200 mg, 0.88 mmol),4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(447 mg, 1.76 mmol), KOAc (259 mg, 2.64 mmol), Pd₂(dba)₃ (82 mg, 0.09mmol), X-Phos (52 mg, 0.11 mmol) in dioxane (5 mL) was bubbled with N₂for 5 min and then stirred at 70° C. for 12 hr. The rxn mixture wasconcentrated, treated with DCM (30 mL), washed with H₂O (30 mL) andbrine (30 mL), dried over Na₂SO₄, filtered and concentrated. The residuewas purified by column chromatog (PE:EA=20:1˜5:1) to give the titlecompound (130 mg, 54%) as a gray solid. ¹H NMR (CDCl₃, 400 MHz): δ 7.73(s, 1H) 7.62 (s, 1H) 7.01 (s, 1H) 3.68 (s, 3H) 1.35 (s, 12H). LCMS(M+H)⁺: 276.

Step 2:6-methyl-4-[5-(methylsulfonylmethyl)-2-(2,2,2-trifluoroethoxy)phenyl]furo[2,3-c]pyridin-7-one

A mixture of2-bromo-4-(methylsulfonylmethyl)-1-(2,2,2-trifluoroethoxy)benzene (100mg, 0.29 mmol),6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)furo[2,3-c]pyridin-7-one(96 mg, 0.35 mmol), K₃PO₄ (184 mg, 0.87 mmol), Pd(dppf)Cl₂ (22 mg, 10%)in dioxane/H₂O (2 mL/1 mL) was bubbled with N₂ for 5 min. The sealedvial was heated at 70° C. for 2 hr. The rxn mixture was filtered througha short plug of celite; the celite plug was washed with EtOAc (15 mL).The filtrate was washed with H₂O and brine; the organic layer was driedover Na₂SO₄, filtered and concentrated in vacuo. The resulting residuewas purified by prep-HPLC to afford the title compound (40 mg, 33%) asan off-white solid. ¹H NMR (CDCl₃, 400 MHz): δ 7.76 (d, J=2.0 Hz, 1H)7.53 (d, J=2.0 Hz, 1H) 7.41-7.38 (m, 1H) 7.37 (s, 1H) 7.02 (d, J=8.4,1H) 6.72 (d, J=2.0 Hz, 2H) 4.37 (q, J=8.0 Hz, 2H) 4.27 (s, 2H) 3.73 (s,3H) 2.89 (s, 3H). LCMS (M+H)⁺: 416.

Example 259:4-[3-(cyclopropylmethoxy)-6-methylsulfonylpyridin-2-yl]-6-methylfuro[2,3-c]pyridin-7-one

A mixture of6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)furo[2,3-c]pyridin-7-one(50 mg, 0.18 mmol),3-(cyclopropylmethoxy)-2-iodo-6-methylsulfonylpyridine (53 mg, 0.15mmol), K₃PO₄ (114 mg, 0.54 mmol), Pd(dppf)Cl₂ (13 mg, 0.018 mmol) indioxane (5 mL) was bubbled with N₂ for 5 min and then stirred at 70° C.for 12 hr. The rxn mixture was concentrated, treated with DCM (30 mL),washed with H₂O (30 mL) and brine (30 mL), dried over Na₂SO₄, filteredand concentrated. The residue was purified by prep-HPLC to give thetitle compound (35 mg, yield: 52%) as an off-white solid. ¹H NMR (CDCl₃,400 MHz): δ 8.42 (s, 1H) 8.10 (s, 1H) 7.81 (d, J=1.6 Hz, 1H) 7.51 (s,1H) 6.66 (d, J=1.6 Hz, 1H) 4.08 (d, J=7.6 Hz, 2H) 3.77 (s, 3H) 3.26 (s,3H) 1.26-1.19 (m, 1H) 0.68-0.63 (m, 2H) 0.37-0.33 (m, 2H). LCMS (M+H)⁺:375.

Example 260:2-chloro-4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-6-methylfuro[2,3-c]pyridin-7-oneStep 1: 2-chloro-7-methoxyfuro[2,3-c]pyridine

A 0.13 M soln of 7-methoxyfuro[2,3-c]pyridine (250 mg, 1.7 mmol) in THFstirred at −78° C. under an atmosphere of N₂ was treated with n-BuLi(1.6M in hexanes, 450 μL, 5.2 mmol) dropwise over 30 sec. The mixturewas warmed gradually to −15° C. over a period of 7-10 min. After 1 hr at−15° C., the mixture was cooled to −65° C. and was treated with a 0.26 Msoln of hexachloroethane (473 mg, 2 mmol) in THF by dropwise additionover 3 min. After stirring at −65° C. for 15 min, the mixture wasgradually warmed to room temp. After the mixture was allowed to stirovernight, it was quenched with H₂O (5 mL) and extracted with EtOAc(3×15 ml). The combined organic layers were washed brine (10 mL), driedover Na₂SO₄, filtered and concentrated in vacuo. The resulting residuewas purified by silica gel CC using a gradient of EtOAc (5 to 30%) inhexanes to afford the title compound (266 mg, 87%) as an amber oil. ¹HNMR (400 MHz, DMSO-d₆): δ ppm 3.99-4.08 (m, 3H) 7.13 (s, 1H) 7.25 (d,J=5.31 Hz, 1H) 7.95 (d, J=5.31 Hz, 1H). LCMS (M+H)⁺: 184.

Step 2: 2-chlorofuro[2,3-c]pyridin-7-ol

A 0.25M soln of 2-chloro-7-methoxyfuro[2,3-c]pyridine (263 mg, 1.4 mmol)in DCM stirred at −0° C. under an atmosphere of N₂ was treated with BBr₃(1 M in DCM, 4.3 mL, 4.3 mmol) dropwise over 5 min. The mixture wasallowed to warm gradually to room temp. After the mixture was allowed tostir overnight, it was poured into ice-water and extracted with DCM(3×15 mL). The combined organic layers were washed with H₂O and brine(10 mL), dried over Na₂SO₄, filtered and concentrated in vacuo. Theresulting residue was purified by silica gel CC using a gradient ofEtOAc (15 to 75%) in hexanes to afford the title compound (115 mg, 47%)as light yellow solid. LCMS (M+H)⁺: 170.

Step 3: 4-bromo-2-chlorofuro[2,3-c]pyridin-7-ol

A 0.15 M soln of 2-chlorofuro[2,3-c]pyridin-7-ol (113 mg, 0.7 mmol) inDMF stirred in the dark at 0° C. under an atmosphere of N₂ was treatedwith NBS (120 mg, 0.7 mmol) in three equal portions. The icebath wasremoved; the mixture was stirred at room temp for 3 hr. The rxn mixturewas treated with a 10% aq soln of sodium thiosulfate (5 ml) and wasextracted with EtOAc (3×30 mL). The combined organic layers were washedwith H₂O (15 mL), brine (20 mL), dried over Na₂SO₄, filtered, andconcentrated in vacuo. The residue was purified by chromatography onsilica gel (hexanes:EtOAc=4:1) to afford the title compound (145 mg,87%) as a white solid. LCMS (M+H)⁺: 249.

Step 4: 4-bromo-2-chloro-6-methylfuro[2,3-c]pyridin-7-one

A 0.2 M soln of 4-bromo-2-chlorofuro[2,3-c]pyridin-7-ol (143 mg, 0.6mmol) and K₂CO₃ (200 mg, 1.45 mmol) in DMF stirred at 0° C. under N₂ wastreated with MeI (99 mg, 0.7 mmol). The icebath was removed and themixture stirred at room temp overnight. The rxn mixture was treated H₂O(15 mL) and extracted with EtOAc (3×10 mL). The combined organic layerswere washed with H₂O (15 mL), brine (20 mL), dried over Na₂SO₄,filtered, and concentrated in vacuo. The residue was purified bychromatography on silica gel using a gradient of EtOAc (10% to 100%) inhexanes to afford the title compound (113 mg, 85%) as a white solid.LCMS (M+H)⁺: 263.

Step 5:2-chloro-4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-6-methylfuro[2,3-c]pyridin-7-one

A mixture of2-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(33 mg, 0.09 mmol), 4-bromo-2-chloro-6-methylfuro[2,3-c]pyridin-7-one(25 mg, 0.09 mmol), K₃PO₄ (50 mg, 0.24 mmol), Pd(dppf)Cl₂ (7 mg, 10%) indioxane/H₂O (700 μL/70 μL) was bubbled with N₂ for 5 min. The sealedvial was stirred at 70° C. for 90 min. The rxn mixture was filteredthrough a short plug of celite; the celite plug was washed with EtOAc(10 mL). The filtrate was washed with H₂O and brine; the organic layerwas dried over Na₂SO₄, filtered and concentrated in vacuo to afford atan residue. The resulting residue was purified by prep-HPLC to affordthe title compound (27 mg, 69%) as an off-white solid. ¹H NMR (400 MHz,DMSO-d₆): δ ppm 0.23-0.34 (m, 2H) 0.44-0.55 (m, 2H) 1.00-1.13 (m, 1H)3.19-3.24 (m, 3H) 3.61 (s, 3H) 3.94-4.05 (m, 2H) 6.82-6.89 (m, 1H)7.10-7.16 (m, 1H) 7.26-7.35 (m, 1H) 7.70-7.78 (m, 1H) 7.87-7.94 (m, 1H).LCMS (M+H)⁺: 409.

Example 261:2-fluoro-4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-6-methylfuro[2,3-c]pyridin-7-oneStep 1: 2-fluoro-7-methoxyfuro[2,3-c]pyridine

The title compound was prepared in a manner similar to step 1 of Example260, by substituting N-Fluorobenzenesulfonamide for hexachloroethane. ¹HNMR (400 MHz, DMSO-d₆): δ ppm 4.01 (s, 3H) 6.46 (m, 1H) 7.25 (d, J=5.4Hz, 1H) 7.96 (d, J=5.4 Hz, 1H). LCMS (M+H)⁺: 168.

Step 2: 2-fluorofuro[2,3-c]pyridin-7-ol

The title compound was prepared in a manner similar to step 2 of Example260, by substituting 2-fluoro-7-methoxyfuro[2,3-c]pyridine for2-chloro-7-methoxyfuro[2,3-c]pyridine. LCMS (M+H)⁺: 154.

Step 3: 4-bromo-2-fluorofuro[2,3-c]pyridin-7-ol

The title compound was prepared in a manner similar to step 3 of Example260, by substituting 2-fluorofuro[2,3-c]pyridin-7-ol for2-chlorofuro[2,3-c]pyridin-7-ol. LCMS (M+H)⁺: 233.

Step 4: 4-bromo-2-fluoro-6-methylfuro[2,3-c]pyridin-7-one

The title compound was prepared in a manner similar to step 4 of Example260, by substituting 4-bromo-2-fluorofuro[2,3-c]pyridin-7-ol for4-bromo-2-chlorofuro[2,3-c]pyridin-7-ol. LCMS: (M+H)⁺247.

Step 5:2-fluoro-4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-6-methylfuro[2,3-c]pyridin-7-one

A mixture ofN-[6-(cyclopropylmethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl]ethanesulfonamide(31 mg, 0.08 mmol), 4-bromo-2-fluoro-6-methylfuro[2,3-c]pyridin-7-one(20 mg, 0.08 mmol), K₃PO₄ (36 mg, 0.17 mmol), Pd(dppf)Cl₂ (6 mg, 8%) indioxane/H₂O (830 μL/100 μL) was bubbled with N₂ for 10 min. The sealedvial was stirred at 67° C. for 90 min. The rxn mixture was filteredthrough a short plug of celite; the celite plug was washed with EtOAc(15 mL). The filtrate was washed with H₂O and brine; the organic layerwas dried over Na₂SO₄, filtered and concentrated in vacuo to afford atan residue. The resulting residue was purified by CC using MeOH (0% to2%) in DCM. The fractions were combined and concentrated in vacuo toafford a white solid (10 mg). The solid had a minor impurity (LCMS(M+H)⁺: 578); therefore, it was diluted in MeOH (1 mL) and 1N NaOH(aq)(500 μL) and purified by prep-HPLC to afford the title compound (6 mg,17%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ ppm 0.28 (m, 2H)0.43-0.58 (m, 2H) 0.56-0.58 (m, 1H) 1.24 (m, 3H) 3.09 (m, 2H) 3.60 (s,3H) 4.12 (m, 2H) 6.16-6.34 (m, 1H) 7.52-7.72 (m, 1H) 7.77 (s, 1H)7.90-8.14 (m, 1H) 9.37-10.62 (bs, 1H). LCMS (M+H)⁺: 422.

Example 262:N-[5-(2,4-difluorophenoxy)-4-(6-methyl-7-oxofuro[2,3-c]pyridin-4-yl)pyrimidin-2-yl]methanesulfonamideStep 1:4-[5-(2,4-difluorophenoxy)-2-methylsulfonylpyrimidin-4-yl]-6-methylfuro[2,3-c]pyridin-7-one

A mixture of 4-chloro-5-(2,4-difluorophenoxy)-2-methylsulfonylpyrimidine(155 mg, 0.48 mmol), 4-bromo-2-fluoro-6-methylfuro[2,3-c]pyridin-7-one(120 mg, 0.44 mmol), NaHCO₃ (92 mg, 1.1 mmol), Pd(dppf)Cl₂ (32 mg, 10%)in dioxane/H₂O (4 mL/200 μL) was bubbled with N₂ for 7 min. The sealedvial was stirred at 70° C. for 8 hr. LCMS analysis showed completeconsumption of the limiting reagent. The rxn mixture was filteredthrough a short plug of celite; the celite plug was washed with DCM. Thefiltrate was concentrated in vacuo. The resulting residue was purifiedby CC using EtOAc (10 to 100%) in DCM to afford the title compound (151mg, 79%) as a yellow solid. LCMS (M+H)⁺: 434.

Step 2:N-[5-(2,4-difluorophenoxy)-4-(6-methyl-7-oxofuro[2,3-c]pyridin-4-yl)pyrimidin-2-yl]methanesulfonamide

A soln of methanesulfonamide (61 mg, 0.65 mmol) in DMF (2 mL) stirred at0° C. under N₂ was treated with NaH (99 mg, 0.7 mmol). After the icebathwas removed, the mixture was stirred at room temp for 15 min. Theresulting suspension was treated with a soln of4-[5-(2,4-difluorophenoxy)-2-methylsulfonylpyrimidin-4-yl]-6-methylfuro[2,3-c]pyridin-7-one(70 mg, 0.16 mmol) in DMF (1 mL). After the N₂ inlet was removed, thecapped mixture was heated to 70° C. for 3 hr. After cooling to 0° C.,the rxn mixture was stirred vigorously and treated H₂O (500 μL). After 5min, the cooled mixture was treated with 1N HCl_((aq)) (1 mL). Theresulting suspension was filtered; the filter cake was washed withadditional 1N HCl_((aq)) (1 mL) and isopropyl ether (5 mL) to afford thetitle compound (50 mg, 70%) as an off-white solid. ¹H NMR (400 MHz,DMSO-d6): δ ppm 3.34 (s, 3H) 3.60 (s, 3H) 7.06 (m, 1H) 7.28 (m, 1H) 7.49(m, 1H) 7.80 (s, 1H) 8.23 (s, 1H) 8.43 (m, 2H) 11.50 (bs, 1H). LCMS(M+H)⁺: 449.

Example 263:N-[5-(2,4-difluorophenoxy)-4-(6-methyl-7-oxofuro[2,3-c]pyridin-4-yl)pyrimidin-2-yl]ethanesulfonamide

The title compound (46 mg, 62%) was prepared in a manner similar to step2 of Example 262, by substituting ethanesulfonamide formethanesulfonamide. ¹H NMR (400 MHz, DMSO-d₆): δ ppm 1.20-1.27 (m, 3H)3.43-3.57 (m, 2H) 3.57-3.67 (s, 3H) 7.00-7.13 (m, 1H) 7.20-7.37 (m, 1H)7.41-7.54 (m, 1H) 7.72-7.87 (m, 1H) 8.15-8.28 (m, 1H) 8.30-8.49 (m, 2H)11.25-11.48 (bs, 1H). LCMS: (M+H)⁺463.

Example 264:N-[5-(cyclopropylmethoxy)-4-(6-methyl-7-oxofuro[2,3-c]pyridin-4-yl)pyrimidin-2-yl]ethanesulfonamideStep 1:4-[5-(cyclopropylmethoxy)-2-methylsulfonylpyrimidin-4-yl]-6-methylfuro[2,3-c]pyridin-7-one

The title compound was prepared in a manner similar to step 1 of Example262, by substituting4-chloro-5-(cyclopropylmethoxy)-2-methylsulfonylpyrimidine for4-chloro-5-(2,4-difluorophenoxy)-2-methylsulfonylpyrimidine. LCMS(M+H)⁺: 376.

Step 2:N-[5-(cyclopropylmethoxy)-4-(6-methyl-7-oxofuro[2,3-c]pyridin-4-yl)pyrimidin-2-yl]ethanesulfonamide

The title compound was prepared in a manner similar to step 2 of Example262, by substituting ethanesulfonamide for methanesulfonamide and bysubstituting4-[5-(cyclopropylmethoxy)-2-methylsulfonylpyrimidin-4-yl]-6-methylfuro[2,3-c]pyridin-7-onefor4-[5-(2,4-difluorophenoxy)-2-methylsulfonylpyrimidin-4-yl]-6-methylfuro[2,3-c]pyridin-7-one.LCMS (M+H)⁺: 405.

Example 265:4-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-6-methyl-7-oxothieno[2,3-c]pyridine-2-carboxamideStep 1: methyl 4-bromo-6-methyl-7-oxothieno[2,3-c]pyridine-2-carboxylate

To a soln of methyl 4-bromo-7-hydroxythieno[2,3-c]pyridine-2-carboxylate(300 mg, 1.04 mmol) stirred at 0° C. in DMF (6.6 mL) under N₂ was addedK₂CO₃ (358 mg, 2.6 mmol). After stirring at 0° C. for 15 min, methyliodide (177 mg, 1.3 mmol) was added dropwise. The icebath was removed,and mixture was stirred at room temp for 20 min, 50° C. for 2 hr, androom temp for another 10 hr. The rxn mixture was treated with H₂O (8 mL)and extracted with EtOAc (30 mL×3). The combined organic layers werewashed with brine (30 mL), dried over Na₂SO₄, filtered, and concentratedin vacuo. The residue was purified by silica gel chromatography using agradient of EtOAc (10 to 100%) in DCM to afford the title compound (284mg, 90%) as a white solid. LCMS (M+H)⁺: 303.

Step 2: 4-bromo-6-methyl-7-oxothieno[2,3-c]pyridine-2-carboxamide

Using a sealed tube, a soln of methyl4-bromo-6-methyl-7-oxothieno[2,3-c]pyridine-2-carboxylate (250 mg, 65mmol) in MeOH (6 mL) stirred at room temp was treated with 2N NH₃ inMeOH (8 ml). The sealed tube was heated to 45° C. for 60 hr. Aftercooling to 0° C., the resulting suspension was filtered; the filter cakewas washed with cooled (0° C.) MeOH (3 mL) and isopropyl ether (3 mL) toafford the title compound (215 mg, 95%) as a white solid. LCMS (M+H)⁺:288.

Step 3:4-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-6-methyl-7-oxothieno[2,3-c]pyridine-2-carboxamide

A mixture of2-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(77 mg, 0.22 mmol),4-bromo-6-methyl-7-oxothieno[2,3-c]pyridine-2-carboxamide (50 mg, 0.18mmol), K₃PO₄ (93 mg, 0.44 mmol), Pd(dppf)Cl₂ (13 mg, 10%) in dioxane/H₂O(1.6 mL/160 μL) was bubbled with N₂ for 5 min. The sealed vial wasstirred at 65° C. for 3 hr. The rxn mixture was filtered through a shortplug of celite; the celite plug was washed with EtOAc (15 mL). Thefiltrate was washed with H₂O and brine; the organic layer was dried overNa₂SO₄, filtered and concentrated in vacuo to afford a tan residue. Theresulting residue was purified by prep-HPLC to afford the title compound(20 mg, 26%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ ppm 0.20 (m,2H) 0.36 (m, 2H) 0.98 (m, 1H) 1.14 (m, 3H) 3.21-3.31 (m, 2H) 3.61 (s,3H) 3.98 (m, 2H) 7.38 (d, J=8.6 Hz, 1H) 7.65-7.75 (m, 3H) 7.78 (d, J=2.0Hz, 1H) 7.91 (dd, J=8.6, 2.0 Hz, 1H) 8.24 (s, 1H). LCMS (M+H)⁺: 447.

Example 266:4-[2-(cyclopropylmethoxy)-5-(ethylsulfonylamino)phenyl]-6-methyl-7-oxothieno[2,3-c]pyridine-2-carboxamide

The title compound was prepared in a manner similar to step 3 of Example265, by substitutingN-[4-(cyclopropylmethoxy)-3-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethane-1-sulfonamidefor2-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.¹H NMR (400 MHz, DMSO-d₆): δ ppm 0.09-0.19 (m, 2H) 0.27-0.39 (m, 2H)0.86-1.02 (m, 1H) 1.18-1.27 (m, 3H) 2.97-3.09 (m, 2H) 3.59 (s, 3H)3.77-3.86 (m, 2H) 7.07-7.16 (m, 2H) 7.21-7.27 (m, 1H) 7.53-7.58 (m, 1H)7.61-7.67 (m, 1H) 7.67-7.72 (m, 1H) 8.19-8.30 (m, 1H) 9.46-9.60 (m, 1H).LCMS (M+H)⁺: 462.

Example 267:4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-6-methyl-7-oxothieno[2,3-c]pyridine-2-carboxamide

The title compound was prepared in a manner similar to step 3 of Example265, by substituting2-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolanefor2-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.¹H NMR (400 MHz, DMSO-d₆): δ ppm 0.11-0.26 (m, 2H) 0.27-0.41 (m, 2H)0.89-1.05 (m, 1H) 3.21 (s, 3H) 3.61 (s, 3H) 3.91-4.04 (m, 2H) 7.34-7.41(m, 1H) 7.63-7.76 (m, 3H) 7.81-7.88 (m, 1H) 7.92-7.99 (m, 1H) 8.21-8.29(m, 1H). LCMS (M+H)⁺: 433.

Example 268:4-[2-(cyclopropylmethoxy)-5-(ethylsulfonylamino)pyridin-3-yl]-6-methyl-7-oxothieno[2,3-c]pyridine-2-carboxamide

The title compound was prepared in a manner similar to step 3 of Example265, by substitutingN-[6-(cyclopropylmethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl]ethane-sulfonamidefor2-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-4,4,5,5-tetramethyl-1,3,2-di-oxaborolane.¹H NMR (400 MHz, DMSO-d₆): δ ppm 0.17-0.35 (m, 2H) 0.39-0.57 (m, 2H)1.23 (m, 4H) 3.00-3.17 (m, 2H) 3.60 (s, 3H) 4.01-4.26 (m, 2H) 6.11-6.40(m, 1H) 7.52-7.69 (m, 1H) 7.74-7.84 (m, 1H) 7.94-8.09 (m, 1H) 9.14-10.31(m, 1H). LCMS: (M+H)⁺463.

Example 269:N-[4-(2,4-difluorophenoxy)-3-(2,6-dimethyl-7-oxofuro[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamideStep 1: 7-methoxy-2-methylfuro[2,3-c]pyridine

To a soln of 7-methoxyfuro[2,3-c]pyridine (2.9 g, 19.6 mmol) in THF (20mL) stirred under Ar was added n-BuLi (7.8 mL, 19.6 mmol) at −78° C.;the mixture was transferred to a −30° C. icebath and was stirred for 2hr. The mixture was cooled to −78° C. and MeI (4.2 g, 29.4 mmol) wasadded. After the mixture was stirred at room temp for 18 hr, the rxnmixture was quenched with H₂O (30 mL) and extracted with DCM (50 mL×3).The combined organic layers were washed with brine (30 mL×3), dried overNa₂SO₄ and concentrated in vacuo to afford the title compound (3.2 g,100%) as a yellow solid. The material was carried forward without anyfurther purification. LCMS (M+H)⁺: 164.

Step 2: 4-bromo-7-methoxy-2-methylfuro[2,3-c]pyridine

A soln of 7-methoxy-2-methylfuro[2,3-c]pyridine (3.2 g, 19.6 mmol) inACN (30 mL) was treated with NBS (3.5 g, 19.7 mmol). After the mixturewas stirred at room temp for 18 hr, it was concentrated in vacuo andpurified by silica gel chromatography (PE:EA=30:1˜5:1) to afford thetitle compound (3.0 g, 64%) as a yellow solid. LCMS (M+H)⁺: 243.

Step 3: 4-bromo-2-methyl-6H-furo[2,3-c]pyridin-7-one

To a mixture of 4-bromo-7-methoxy-2-methylfuro[2,3-c]pyridine (3.0 g,12.4 mmol) in DCM (30 mL) was stirred at 0° C. under N₂ was added BBr₃(15.5 g, 62.0 mmol) dropwise. The mixture was stirred at 0° C. for 3 hr.The mixture was concentrated in vacuo to afford the title compound (2.50g, 88%). The material was immediately used in the next step without anyfurther purification. LCMS (M+H)⁺: 229.

Step 4: 4-bromo-2,6-dimethylfuro[2,3-c]pyridin-7-one

The title compound was prepared in a manner similar to step 2 of Example252, by substituting 4-bromo-2-methyl-6H-furo[2,3-c]pyridin-7-one for4-bromo-6H,7H-furo[2,3-c]-pyridin-7-one. ¹H NMR (CDCl₃, 400 MHz): δ 7.26(s, 1H), 6.32 (s, 1H), 3.64 (s, 3H), 2.49 (s, 3H). LCMS (M+H)⁺: 243.

Step 5:N-[4-(2,4-difluorophenoxy)-3-(2,6-dimethyl-7-oxofuro[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamide

A mixture of 4-bromo-2,6-dimethylfuro[2,3-c]pyridin-7-one (200 mg, 0.83mol),N-[4-(2,4-difluorophenoxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethanesulfonamide(364 mg, 0.99 mmol), Pd(dppf)Cl₂ (66 mg, 0.09 mmol), K₃PO₄ (527 mg, 2.49mmol) in dioxane/H₂O (4 mL/1 mL) was bubbled with Ar for 5 min. Themixture was heated at 70° C. for 18 hr. After cooling to room temp, therxn mixture was poured into H₂O (10 mL) and extracted with EtOAc (40mL×3). The combined organic layers were washed with brine (20 mL×2),dried over Na₂SO₄, filtered, and concentrated in vacuo. The residue waspurified by prep-HPLC to afford the title compound (49 mg, 12%) as ayellow solid. ¹H NMR (CDCl₃, 400 MHz): δ 7.35-7.33 (m, 2H) 7.12 (m, 1H)6.95-6.89 (m, 2H) 6.81 (m, 2H) 6.43 (s, 1H) 6.38 (s, 1H) 3.71 (s, 3H)3.16 (q, J=7.2 Hz, 2H) 2.47 (s, 3H) 1.43 (t, J=7.2 Hz, 3H). LCMS (M+H)⁺:475.

Example 270:4-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-2,6-dimethylfuro[2,3-c]pyridine-7-one

The title compound was prepared in a manner similar to step 5 of Example269, by substituting2-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolaneforN-[4-(2,4-difluorophenoxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethanesulfonamide.¹H NMR (CDCl₃, 400 MHz): δ 7.89 (dd, J₁=8.8 Hz, J₂=2.4 Hz, 1H) 7.85 (d,J=2.4 Hz, 1H) 7.34 (s, 1H) 7.09 (d, J=8.8 Hz, 1H) 6.24 (s, 1H) 3.94 (m,2H) 3.78 (s, 3H) 3.14 (q, J=7.2 Hz, 2H) 2.48 (s, 3H) 1.32 (t, J=7.2 Hz,3H) 1.18-1.16 (m, 1H) 0.64-0.59 (m, 2H) 0.32-0.28 (m, 2H). LCMS (M+H)⁺:402.

Example 271:N-[4-(2,4-difluorophenoxy)-3-(5-fluoro-1-methyl-6-oxopyridin-3-yl)phenyl]methanesulfonamide

The title compound was prepared in a manner similar to Example 122,substituting N-[3-bromo-4-(2,4-difluorophenoxy)phenyl]methanesulfonamidefor N-[3-Bromo-4-(2,4-difluoro-phenoxy)phenyl]ethanesulfonamide. ¹H NMR(400 MHz, DMSO-d₆): δ ppm 2.98-3.07 (m, 3H) 3.52-3.60 (m, 3H) 6.80-6.94(m, 1H) 7.10 (s, 1H) 7.14-7.24 (m, 1H) 7.24-7.28 (m, 1H) 7.38-7.51 (m,1H) 7.57-7.66 (m, 1H) 7.76-7.86 (m, 1H) 9.67-9.76 (m, 1H). LCMS (M+H)⁺:425.

Example 272:3-chloro-5-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-1-methylpyridin-2-one

The title compound was prepared in a manner similar to Example 119,substituting3-chloro-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-onefor3-fluoro-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one,and 2-bromo-1-(cyclopropylmethoxy)-4-ethylsulfonylbenzene for2-bromo-1-(cyclopropylmethoxy)-4-methanesulfonylbenzene. LCMS (M+H)⁺:382.

Example 273:5-[5-(2,4-difluorophenoxy)-2-methylsulfonylpyrimidin-4-yl]-1-methyl-3-propan-2-ylpyridin-2-one

The title compound was prepared in three steps. Using conditions similarto those described by Malhotra et al., in Organic Letters 2013, 15(14):3698-3701 (supporting information, compounds 4c and 3a),3,5-dibromo-1-methylpyridin-2-one was alkylated at the 3-position usingisopropylmagnesium bromide to give5-bromo-1-methyl-3-propan-2-ylpyridin-2-one which was then reacted with4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolaneusing conditions similar to those described in Example 248, step 2 togive the pinacol ester,1-methyl-3-propan-2-yl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one.This pinacol ester was then substituted for the pinacol ester of Example149, step 4 and reacted in the same manner to obtain the title compound.LCMS (M+H)⁺: 436.

Example 274:5-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-3-fluoro-1-methylpyridin-2-one

The title compound was prepared in a manner similar to Example 119,substituting 2-bromo-1-(cyclopropylmethoxy)-4-ethylsulfonylbenzene for2-bromo-1-(cyclopropylmethoxy)-4-methanesulfonylbenzene. LCMS (M+H)⁺:366.

Example 275:3-chloro-5-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-1-methylpyridin-2-one

The title compound was prepared in a manner similar to Example 119,substituting3-chloro-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-onefor3-fluoro-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one,andN-(cyclopropylmethyl)-4-ethylsulfonyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)anilinefor 2-bromo-1-(cyclopropylmethoxy)-4-methanesulfonylbenzene. LCMS(M+H)⁺: 381.

Example 276:5-[2-(2,4-difluorophenoxy)-5-(methanesulfonylmethyl)phenyl]-3-(²H₃)methyl-1-methyl-1,2-dihydropyridin-2-one

The title compound was prepared in a manner similar to Example 119,substituting3-(²H₃)methyl-1-methyl-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-dihydropyridin-2-onefor3-fluoro-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one,and 2-bromo-1-(2,4-difluorophen-oxy)-4-(methylsulfonylmethyl)benzene for2-bromo-1-(cyclopropylmethoxy)-4-methanesulfonyl-benzene. ¹H NMR (400MHz, DMSO-d₆): δ ppm 2.93 (s, 3H) 3.49 (s, 3H) 4.42-4.52 (m, 2H)6.81-6.89 (m, 1H) 7.04-7.16 (m, 1H) 7.20-7.29 (m, 1H) 7.30-7.35 (m, 1H)7.43-7.51 (m, 2H) 7.53-7.57 (m, 1H) 7.75-7.82 (m, 1H). LCMS (M+H)⁺: 423.

Example 277:N-[4-(2,4-difluorophenoxy)-3-[5-(²H₃)methyl-1-methyl-6-oxo-1,6-dihydropyridin-3-yl]phenyl]methanesulfonamide

The title compound was prepared in a manner similar to Example 122,substituting N-[3-bromo-4-(2,4-difluorophenoxy)phenyl]methanesulfonamidefor N-[3-Bromo-4-(2,4-difluoro-phen-oxy)phenyl]ethanesulfonamide, and3-(²H₃)methyl-1-methyl-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-dihydropyridin-2-onefor3-fluoro-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one.¹H NMR (400 MHz, DMSO-d₆): δ ppm 2.98-3.05 (m, 3H) 3.44-3.50 (m, 3H)6.84-6.92 (m, 1H) 7.01-7.18 (m, 3H) 7.21-7.26 (m, 1H) 7.38-7.47 (m, 1H)7.47-7.51 (m, 1H) 7.73-7.79 (m, 1H) 9.61-9.78 (bs, 1H). LCMS (M+H)⁺:424.

Example 278:N-[4-(2,4-difluorophenoxy)-3-[5-(²H₃)methyl-1-methyl-6-oxo-1,6-dihydropyridin-3-yl]phenyl]ethane-1-sulfonamide

The title compound was prepared in a manner similar to Example 122,substituting3-(²H₃)methyl-1-methyl-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-dihydropyridin-2-onefor3-fluoro-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one.¹H NMR (400 MHz, DMSO-d₆): δ ppm 1.19-1.25 (m, 3H) 3.05-3.16 (m, 2H)3.45-3.49 (m, 3H) 6.85-6.92 (m, 1H) 6.99-7.20 (m, 4H) 7.23 (m, 1H)7.38-7.46 (m, 1H) 7.46-7.50 (m, 1H) 7.71-7.79 (m, 1H) 9.60-9.85 (m, 1H).LCMS (M+H)⁺: 438.

Example 279:N-[3-(5-cyclopropyl-1-methyl-6-oxopyridin-3-yl)-4-(2,4-difluorophenoxy)phenyl]methanesulfonamide

The title compound was prepared in a manner similar to Example 122,substituting3-cyclopropyl-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-onefor3-fluoro-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one,and N-[3-bromo-4-(2,4-difluorophenoxy)phenyl]methanesulfonamide forN-[3-bromo-4-(2,4-difluorophenoxy)phenyl]ethanesulfonamide. ¹H NMR (400MHz, DMSO-d₆): δ ppm 0.46-0.54 (m, 2H) 0.77-0.88 (m, 2H) 1.93-2.07 (m,1H) 2.98-3.05 (m, 3H) 3.44-3.51 (m, 3H) 6.89-6.95 (m, 1H) 7.00-7.12 (m,3H) 7.13-7.19 (m, 1H) 7.21-7.25 (m, 1H) 7.39-7.48 (m, 1H) 7.71 (s, 1H)9.56-9.82 (bs, 1H). LCMS (M+H)⁺: 447.

Example 280:3-cyclopropyl-5-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-1-methylpyridin-2-one

The title compound was prepared in a manner similar to Example 119,substituting3-cyclopropyl-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-onefor3-fluoro-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-oneand 2-bromo-1-(cyclo-propylmethoxy)-4-ethylsulfonylbenzene for2-bromo-1-(cyclopropylmethoxy)-4-methanesulfonyl-benzene. ¹H NMR (400MHz, DMSO-d₆): δ ppm 0.33-0.41 (m, 2H) 0.55-0.61 (m, 2H) 0.63-0.69 (m,2H) 0.83-0.91 (m, 2H) 1.07-1.14 (m, 3H) 1.19-1.25 (m, 1H) 2.01-2.12 (m,1H) 3.23-3.30 (m, 2H) 3.52 (s, 3H) 3.92-4.00 (m, 2H) 7.22-7.29 (m, 2H)7.70-7.80 (m, 3H). LCMS (M+H)⁺: 388.

Example 281:N-[4-(2,4-difluorophenoxy)-3-(1-methyl-6-oxo-5-pyrrolidin-1-ylpyridin-3-yl)phenyl]methanesulfonamide

The title compound was prepared in a manner similar to Example 122,substituting1-methyl-3-pyrrolidin-1-yl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-onefor3-fluoro-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-oneand N-[3-bromo-4-(2,4-difluorophenoxy)phenyl]methanesulfonamide forN-[3-bromo-4-(2,4-difluorophenoxy)phenyl]ethanesulfonamide. LCMS (M+H)⁺:476.

Example 282:5-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-1-methyl-3-pyrrolidin-1-ylpyridin-2-one

The title compound was prepared in a manner similar to Example 119,substituting1-methyl-3-pyrrolidin-1-yl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-onefor3-fluoro-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one,and 2-bromo-1-(cyclo-propylmethoxy)-4-ethylsulfonylbenzene for2-bromo-1-(cyclopropylmethoxy)-4-methane-sulfonyl-benzene. ¹H NMR (400MHz, DMSO-d₆): δ ppm 0.33-0.40 (m, 2H) 0.53-0.61 (m, 2H) 1.08-1.14 (m,3H) 1.20-1.29 (m, 1H) 1.81-1.90 (m, 4H) 3.23-3.30 (m, 2H) 3.35-3.35 (m,1H) 3.35-3.40 (m, 3H) 3.48 (s, 3H) 3.94-4.03 (m, 2H) 6.60-6.66 (m, 1H)7.21-7.28 (m, 1H) 7.31-7.38 (m, 1H) 7.68-7.79 (m, 2H). LCMS (M+H)⁺: 417.

Example 283:N-[4-(2,4-difluorophenoxy)-3-(5-ethynyl-1-methyl-6-oxopyridin-3-yl)phenyl]ethanesulfonamideStep 1: 5-bromo-3-iodo-1-methylpyridin-2-one

To a soln of 5-bromo-3-iodo-1H-pyridin-2-one (12.0 g, 40.01 mmol)stirred in dry DMF (120 mL) at 0° C. under N₂ was added NaH (2.4 g,60.02 mmol, 60% in mineral oil). After the mixture was stirred at 0° C.for 1 hr, iodomethane (11.4 g, 80.03 mmol) was added dropwise. Theicebath was removed, and the rxn was stirred at room temp for 1 hr. Themixture was poured into ice water (200 mL); the resulting precipitatewas filtered, collected and dried to give the title compound (12 g, 95%)as a light yellow solid. The material was used without any furtherpurification. ¹H NMR (CDCl₃, 400 MHz): δ 8.01 (d, J=3.2 Hz, 1H), 7.46(d, J=3.2 Hz, 1H), 3.60 (s, 3H). LCMS (M+H)⁺: 315.

Step 2: 5-bromo-1-methyl-3-(2-trimethylsilylethynyl)pyridin-2-one

A mixture of 5-bromo-3-iodo-1-methylpyridin-2-one (8.0 g, 25.48 mmol),ethynyltri-methylsilane (2.7 g, 27.52 mmol), CuI (485 mg, 2.55 mmol),Pd(PPh₃)₂Cl₂ (1.79 g, 2.55 mmol) and triethylamine (12.9 g, 127.4 mmol)in dry THF (100 mL) was heated to 60° C. under N₂ for 2 hr. The mixturewas concentrated and the residue was purified by CC on silica gel(PE:EA=5:1) to give the title compound (6 g, 82%) as a yellow solid. ¹HNMR (CDCl₃, 400 MHz): δ 7.61 (d, J=2.4 Hz, H), 7.42 (d, J=2.4 Hz, 1H),3.54 (s, 3H), 0.25 (s, 9H). LCMS (M+H)⁺: 285.

Step 3:1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(2-trimethylsilylethynyl)pyridin-2-one

A mixture of 5-bromo-1-methyl-3-(2-trimethylsilylethynyl)pyridin-2-one(9.0 g, 31.67 mmol),4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(20.1 g, 79.16 mmol), Pd₂(dba)₃ (1.8 g, 3.17 mmol), X-Phos (1.5 g, 3.17mmol) and KOAc (18.65 g, 189.99 mmol) in anhydrous dioxane (200 mL) wasstirred at 70° C. under Ar for 12 hr. After the mixture was concentratedin vacuo, the residue was purified by CC (PE:EA=4:1) to give the titlecompound (3.5 g, 33%) as an off-white solid. ¹H NMR (CDCl₃, 400 MHz): δ7.88 (d, J=2.0 Hz, 1H), 7.75 (d, J=2.0 Hz, 1H), 3.56 (s, 3H), 1.31 (s,12H), 0.25 (s, 9H). LCMS (M+H)⁺: 332 and 250.

Step 4:N-[4-(2,4-difluorophenoxy)-3-[1-methyl-6-oxo-5-(2-trimethylsilylethynyl)pyridine-3-yl]phenyl]ethanesulfonamide

A mixture of1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(2-trimethyl-silylethynyl)pyridin-2-one(200 mg, 0.6 mmol),N-[3-Bromo-4-(2,4-difluorophenoxy)phenyl]-ethanesulfonamide (197 mg, 0.5mmol), Pd(dppf)Cl₂ (37 mg, 0.05 mmol), and K₃PO₄ (267 mg, 1.26 mmol) indioxane (6 mL) and H₂O (0.6 mL) was stirred at 70° C. under Ar for 12hr. After the mixture was concentrated, the residue was purified by CC(PE:EA=2:1) to give the title compound (100 mg, 38%) as a yellow solid.¹H NMR (CDCl₃, 400 MHz): δ 7.82 (d, J=2.4 Hz, 1H), 7.67 (d, J=2.4 Hz,1H), 7.23 (d, J=2.4 Hz, 1H), 7.16-7.12 (m, 1H), 6.99-6.91 (m, 2H),6.87-6.83 (m, 1H), 6.78 (m, 1H), 6.65 (s, 1H), 3.61 (s, 3H), 3.14 (q,J=7.2 Hz, 2H), 1.42 (t, J=7.2 Hz, 3H), 0.24 (s, 9H). LCMS (M+H)⁺: 517.

Step 5:N-[4-(2,4-difluorophenoxy)-3-(5-ethynyl-1-methyl-6-oxopyridin-3-yl)phenyl]ethanesulfonamide

To a mixture ofN-[4-(2,4-difluorophenoxy)-3-[1-methyl-6-oxo-5-(2-trimethylsilyl-ethynyl)pyridin-3-yl]phenyl]ethanesulfonamide(100 mg, 0.19 mmol) in EtOH (10 mL) was added K₂CO₃ (157 mg, 1.14 mmol).The rxn was stirred at 20° C. for 12 hr and poured into H₂O (30 mL) andextracted with DCM (20 mL×3). The organic phase was washed with brine(20 mL), dried over anhydrous MgSO₄ and concentrated in vacuo. Theresidue was purified by prep-HPLC to afford the title compound (48 mg,56%) as an off-white solid. ¹H NMR (CDCl₃, 400 MHz): δ 7.90 (d, J=2.4Hz, 1H), 7.69 (d, J=2.4 Hz, 1H), 7.26 (d, J=2.8 Hz, 1H), 7.14-7.11 (m,1H), 7.01-6.94 (m, 2H), 6.89-6.86 (m, 1H), 6.77 (d, J=8.8 Hz, 1H), 6.55(s, 1H), 3.67 (s, 3H), 3.34 (s, 1H), 3.14 (q, J=7.2 Hz, 2H), 1.42 (t,J=7.2 Hz, 3H). LCMS (M+H)⁺: 445.

Example 284:5-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-3-ethynyl-1-methylpyridin-2-one

The title compound was prepared in a manner similar to Example 283,substituting 2-bromo-1-(cyclopropylmethoxy)-4-ethylsulfonylbenzene forN-[3-Bromo-4-(2,4-difluorophenoxy)phenyl]ethanesulfonamide in Step 4. ¹HNMR (CDCl₃, 400 MHz): δ 7.93 (d, J=2.4 Hz, 1H), 7.84-7.81 (m, 1H), 7.76(d, J=2.4 Hz, 1H), 7.68 (d, J=2.8 Hz, 1H), 7.03 (d, J=8.4 Hz, 1H), 3.96(d, J=7.2 Hz, 2H), 3.66 (s, 3H), 3.35 (s, 1H), 3.13 (q, J=7.2 Hz, 2H),1.32-1.27 (m, 4H), 0.71-0.67 (m, 2H), 0.40-0.37 (m, 2H). LCMS (M+H)⁺:372.

Example 285:5-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-3-ethynyl-1-methylpyridin-2-one

The title compound was prepared in a manner similar to Example 283,substituting 2-bromo-1-(cyclopropylmethoxy)-4-methylsulfonylbenzene forN-[3-Bromo-4-(2,4-difluorophenoxy)phenyl]ethanesulfonamide in Step 4. ¹HNMR: (CDCl₃, 400 MHz): δ 7.92 (d, J=2.0 Hz, 1H), 7.86 (d, J=8.8 Hz, 1H),7.81 (s, 1H), 7.69 (d, J=1.6 Hz, 1H), 7.04 (d, J=8.4 Hz, 1H), 3.96 (d,J=6.8 Hz, 3H), 3.65 (s, 3H), 3.34 (s, 1H), 3.07 (s, 3H), 1.28-1.27 (m,1H), 0.70-0.68 (m, 2H), 0.38-0.37 (m, 2H). LCMS (M+H)⁺: 358.

Example 286:N-[4-(2,4-difluorophenoxy)-3-(5-ethynyl-1-methyl-6-oxopyridin-3-yl)phenyl]methanesulfonamide

The title compound was prepared in a manner similar to Example 283,substituting N-[3-bromo-4-(2,4-difluorophenoxy)phenyl]methanesulfonamidefor N-[3-Bromo-4-(2,4-difluorophenoxy)phenyl]ethanesulfonamide in Step4. ¹H NMR (CDCl₃, 400 MHz): δ 7.89 (d, J=3.2 Hz, 1H), 7.69 (d, J=3.2 Hz,1H), 7.26-7.25 (m, 1H), 7.15-7.10 (m, 1H), 7.03-6.94 (m, 2H), 6.91-6.84(m, 1H), 6.78 (d, J=11.6 Hz, 1H), 6.45 (s, 1H), 3.66 (s, 3H), 3.35 (s,1H), 3.04 (s, 3H). LCMS (M+H)⁺: 431.

Example 287:5-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-3-(difluoromethoxy)-1-methylpyridin-2-oneStep 1: 5-bromo-3-methoxy-1-methylpyridin-2-one

To a soln of 5-bromo-3-hydroxy-1H-pyridin-2-one (5.00 g, 26.31 mmol) inDMF (100 mL) stirred at 0° C. was added NaH (2.16 g, 53.95 mmol, 60% inmineral oil). After 30 min, iodomethane (9.33 g, 65.78 mmol) was addedover a period of 5 min. After the mixture was stirred at room temp for12 hr, it was quenched with H₂O (20 mL) and extracted with EtOAc (100mL×3). The combined organic layers were washed with brine (100 mL×3),dried over Na₂SO₄, and concentrated in vacuo to give the title compound(5.5 g, 96%). The material was carried forward without furtherpurification. LCMS (M+H)⁺: 219.

Step 2: 5-bromo-3-hydroxy-1-methylpyridin-2-one

To a soln of 5-bromo-3-methoxy-1-methylpyridin-2-one (5.60 g, 25.7 mmol)stirred at 0° C. in DCM (100 mL) was added BBr₃ (12.87 g, 51.4 mmol).The icebath was removed and the mixture was stirred at room temp for 5hr. After the mixture was cooled to 0° C., it was quenched with MeOH (5mL), concentrated to near dryness and purified by CC on silica gel togive title compound (3 g, 57%) as a white solid. ¹H NMR (CDCl3, 400MHz): δ 7.49 (s, 1H), 6.80 (s, 1H), 3.44 (s, 3H). LCMS (M+H)⁺: 205.

Step 3:5-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-3-hydroxy-1-methylpyridin-2-one

To a mixture of 5-bromo-3-hydroxy-1-methylpyridin-2-one (1.00 g, 4.9mmol),2-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(1.80 g, 4.9 mmol) in dioxane (30 mL) and H₂O (5 mL) was added K₃PO₄(3.12 g, 14.7 mmol), Pd(dppf)Cl₂ (358 mg, 0.49 mmol). After purging themixture with N₂, the mixture was stirred at 90° C. under microwaveirridation for 1 hr. After the mixture was filtered, the filtrate wasconcentrated to dryness. The resulting residue was purified by prep-HPLCto give the title compound (0.9 g, 51%) as a purple solid. ¹H NMR(CDCl₃, 400 MHz): δ 7.81 (dd, J₁=8.8 Hz, J₂=2.4 Hz, 1H), 7.77 (d, J=2.4Hz, 1H), 7.16-7.15 (m, 2H), 3.95 (d, J=6.8 Hz, 2H), 3.70 (s, 3H), 3.12(q, J=7.6 Hz, 2H), 1.32-1.27 (m, 4H), 0.70-0.67 (m, 2H), 0.39-0.36 (m,2H). LCMS (M+H)⁺: 364.

Step 4:5-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-3-(difluoromethoxy)-1-methylpyridin-2-one

A mixture of5-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-3-hydroxy-1-methylpyridin-2-one(50 mg, 0.14 mmol), sodium chlorodifluoroacetate (252 mg, 1.65 mmol),K₂CO₃ (70 mg, 0.51 mmol) in dioxane (4 mL) was stirred at 100° C. for 18hr. After the mixture was filtered, the filtrate was concentrated invacuo. The residue was purified by prep-HPLC to give the title compound(16 mg, 28%) as a light pink solid. ¹H NMR (CDCl₃, 400 MHz): δ 7.84 (m,1H) 7.77 (d, J=2.4 Hz, 1H) 7.63 (d, J=2.4 Hz, 1H) 7.49 (d, J=2.4 Hz, 1H)7.04 (m, 1H) 3.95 (m, 2H) 3.69 (s, 3H) 3.13 (m, 3H) 1.33-1.26 (m, 4H)0.72-0.67 (m, 2H) 0.39-0.36 (m, 2H). LCMS (M+H)⁺: 414.

Example 288:5-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-1-methyl-3-(2,2,2-trifluoroethoxy)pyridin-2-one

A mixture of5-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-3-hydroxy-1-methylpyridin-2-one(50 mg, 0.14 mmol), 2,2,2-trifluoroethyl trifluoromethanesulfonate (33mg, 0.14 mmol), Cs₂CO₃ (134.48 mg, 0.42 mmol) in DMF (2 mL) was stirredat 20° C. for 2 hr. After the mixture was filtered, the filtrate wasconcentrated in vacuo. The residue was purified by prep-HPLC to give thetitle compound (29 mg, 47%) as an off-white solid. ¹H NMR (CDCl₃, 400MHz): δ 7.84 (m, 1H), 7.77 (m, 1H), 7.41 (m, 2H), 7.04 (m, 1H), 4.58 (m,2H), 3.95 (m, 2H), 3.70 (s, 3H), 3.14 (m, 2H), 1.33-1.27 (m, 4H),0.72-0.69 (m, 2H), 0.39-0.35 (m, 2H). LCMS (M+H)⁺: 446.

Example 289:N-[3-[5-(difluoromethoxy)-1-methyl-6-oxopyridin-3-yl]-4-(2,4-difluorophenoxy)phenyl]ethanesulfonamideStep 1: 5-bromo-3-(difluoromethoxy)-1-methylpyridin-2-one

The title compound was prepared in a manner similar to step 4 in Example287, substituting 5-bromo-3-hydroxy-1-methylpyridin-2-one for5-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-3-hydroxy-1-methylpyridin-2-one.LCMS (M+H)⁺: 255.

Step 2:N-[3-[5-(difluoromethoxy)-1-methyl-6-oxopyridin-3-yl]-4-(2,4-difluorophenoxy)phenyl]ethanesulfonamide

A mixture of 5-bromo-3-(difluoromethoxy)-1-methylpyridin-2-one (50 mg,0.20 mmol),N-[4-(2,4-difluorophenoxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethanesulfonamide(88 mg, 0.18 mmol), Pd(dppf)Cl₂ (11 mg) and K₃PO₄ (85 mg, 0.40 mmol) indioxane (5 mL) and H₂O (5 drops) was purged with N₂, capped, and heatedto 70° C. for 8 hr. After the mixture was filtered, the filtrate wasconcentrated in vacuo and purified by prep-HPLC to afford the titlecompound (13 mg, 13%) as a white solid. ¹H NMR (CDCl₃, 400 MHz): δ 7.53(m, 2H) 7.25 (m, 1H) 7.05 (m, 1H) 7.12 (m, 1H) 7.02-6.97 (m, 2H)6.97-6.95 (m, 1H) 6.77 (m, 1H) 6.48 (bs, 1H) 3.67 (s, 3H) 3.15 (q, J=7.4Hz, 2H) 1.42 (t, J=7.4 Hz, 3H). LCMS: (M+H)⁺487.

Example 290:N-[4-(2,4-difluorophenoxy)-3-[1-methyl-6-oxo-5-(2,2,2-trifluoroethoxy)pyridin-3-yl]phenyl]ethanesulfonamideStep 1: 5-bromo-1-methyl-3-(2,2,2-trifluoroethoxy)pyridin-2-one

The title compound was prepared in a manner similar to Example 288,substituting 5-bromo-3-hydroxy-1-methylpyridin-2-one for5-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-3-hydroxy-1-methylpyridin-2-one.LCMS (M+H)⁺: 287.

Step 2:N-[4-(2,4-difluorophenoxy)-3-[1-methyl-6-oxo-5-(2,2,2-trifluoroethoxy)pyridine-3-yl]phenyl]ethanesulfonamide

A mixture of 5-bromo-1-methyl-3-(2,2,2-trifluoroethoxy)pyridin-2-one (50mg, 0.18 mmol),N-[4-(2,4-difluorophenoxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethanesulfonamide(79 mg, 0.18 mmol), Pd(dppf)Cl₂ (11 mg) and K₃PO₄ (76 mg, 0.36 mmol) indioxane (5 mL) and H₂O (5 drops) was purged with N₂, capped, and heatedto 70° C. for 8 hr. After the mixture was filtered, the filtrate wasconcentrated in vacuo and purified by prep-HPLC to afford the titlecompound (11 mg, 11%) as a white solid. ¹H NMR (CDCl₃, 400 MHz): δ 7.39(m, 1H) 7.32 (m, 1H) 7.25 (d, J=2.8 Hz, 1H) 7.12 (dd, J₁=2.8 Hz, J₂=8.8Hz, 1H) 6.99-6.93 (m, 2H) 6.88-6.83 (m, 1H) 6.79 (d, J=8.8 Hz, 1H) 6.47(b.s., 1H), 4.56 (m, 2H), 3.65 (s, 3H) 3.15 (q, J=7.2 Hz, 2H) 1.42 (t,J=7.2 Hz, 3H). LCMS (M+H)⁺: 519.

Example 291:3-(difluoromethoxy)-5-[2-(2,4-difluorophenoxy)-5-(ethylsulfonylmethyl)phenyl]-1-methylpyridin-2-one

A mixture of 5-bromo-3-(difluoromethoxy)-1-methylpyridin-2-one (50 mg,0.20 mmol),2-[2-(2,4-difluorophenoxy)-5-(ethylsulfonylmethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(79 mg, 0.18 mmol), Pd(dppf)Cl₂ (11 mg) and K₃PO₄ (76 mg, 0.36 mmol) indioxane (5 mL) and H₂O (5 drops) was purged with N₂, capped, and heatedto 70° C. for 8 hr. After the mixture was filtered, the filtrate wasconcentrated in vacuo and purified by prep-HPLC to afford the titlecompound (21 mg, 22%) as a white solid. ¹H NMR (CDCl₃, 400 MHz): δ 7.62(d, J=2.0 Hz, 1H) 7.54 (d, J=2.0 Hz, 1H) 7.40 (d, J=2.0 Hz, 1H) 7.29 (d,J=2.0 Hz, 1H) 7.09-6.96 (m, 3H) 6.93-6.88 (m, 1H) 6.78 (m, 1H) 4.21 (s,2H) 3.70 (s, 3H) 2.97 (q, J=7.6 Hz, 2H) 1.43 (t, J=7.6 Hz, 3H). LCMS(M+H)⁺: 486.

Example 292:5-[2-(2,4-difluorophenoxy)-5-(ethylsulfonylmethyl)phenyl]-1-methyl-3-(2,2,2-trifluoroethoxy)pyridin-2-one

A mixture of 5-bromo-1-methyl-3-(2,2,2-trifluoroethoxy)pyridin-2-one (50mg, 0.18 mmol),2-[2-(2,4-difluorophenoxy)-5-(ethylsulfonylmethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(88 mg, 0.20 mmol), Pd(dppf)Cl₂ (11 mg) and K₃PO₄ (85 mg, 0.40 mmol) indioxane (5 mL) and H₂O (5 drops) was purged with N₂, capped, and heatedto 70° C. for 8 hr. After the mixture was filtered, the filtrate wasconcentrated in vacuo and purified by prep-HPLC to afford the titlecompound (21 mg, 22%) as a white solid. ¹H NMR (CDCl₃, 400 MHz): δ 7.41(m, 2H) 7.35 (m, 1H) 7.30 (m, 1H) 7.07-6.96 (m, 2H) 6.92-6.87 (m, 1H)6.80 (m, 1H), 4.51 (m, 2H) 4.21 (s, 2H) 3.69 (s, 3H) 2.97 (m, 2H) 1.44(m, 3H). LCMS (M+H)⁺: 518.

Example 293:5-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-1-methyl-3-(1-methylpyrazol-4-yl)oxypyridin-2-oneStep 1: 5-bromo-1-methyl-3-(1-methylpyrazol-4-yl)oxypyridin-2-one

A 0.3M soln of 5-bromo-3-chloro-1-methylpyridin-2-one (124 mg, 0.56mmol) in DMF was treated with Cs₂CO₃ (546 mg, 1.7 mmol). The mixture wassonicated for 30 sec before heating to 140° C. by microwave irradiation(normal) for 150 min. The resulting suspension was diluted with H₂O andextracted with EtOAc (15 mL×3). The combined organic layers were washedwith brine, dried over Na₂SO₄, and concentrated in vacuo. The resultingsolid was purified by silica gel CC using a gradient of EtOAc (5 to 60%)in hexanes to afford the title compound (33 mg, 19%) as a tan solid.LCMS: (M+H)⁺285.

Step 2:5-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-1-methyl-3-(1-methylpyrazol-4-yl)oxypyridin-2-one

A mixture of 5-bromo-1-methyl-3-(1-methylpyrazol-4-yl)oxypyridin-2-one(30 mg, 0.11 mmol),2-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(44 mg, 0.16 mmol), Pd(dppf)Cl₂ (8 mg) and K₃PO₄ (57 mg, 0.26 mmol) indioxane (1.5 mL) and H₂O (200 μL) was purged with N₂, capped, and heatedto 75° C. for 12 hr. After the mixture was filtered through a short bedof celite, the filtrate was concentrated in vacuo and purified byprep-HPLC to afford the title compound (35 mg, 78%) as an off-whitesolid. ¹H NMR (400 MHz, DMSO-d₆): δ ppm 0.12-0.36 (m, 2H) 0.46-0.61 (m,2H) 0.99-1.17 (m, 1H) 3.14-3.23 (m, 3H) 3.55-3.60 (m, 3H) 3.75-3.83 (m,3H) 3.88-3.96 (m, 2H) 7.18-7.32 (m, 2H) 7.32-7.40 (m, 1H) 7.68-7.91 (m,4H). LCMS (M+H)⁺: 430.

Example 294:5-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-1-methyl-3-(1-propan-2-ylpyrazol-4-yl)oxypyridin-2-oneStep 1: 1-propan-2-ylpyrazol-4-ol

A 0.4 M soln of1-propan-2-yl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyrazole(472 mg, 2 mmol) in THF stirred at 0° C. was treated with a 2.5 M aqsoln of NaOH (1.6 mL, 4 mmol) and 30% H₂O_(2(aq)) (453 μI, 4 mmol). Theicebath was removed and the mixture was allowed to stir at room temp for1 hr. After adjustment to pH 3 by the addition of aq 2N H₂SO₄, themixture was extracted with DCM. The combined organic layers were washedwith brine, dried over MgSO₄, filtered, and concentrated in vacuo. Theresulting solid was purified by silica gel CC using EtOAc (5 to 90%) inhexanes to afford the title compound (240 mg, 95%) as a white solid.LCMS (M+H)⁺: 127.

Step 2:5-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-3-iodo-1-methylpyridin-2-one

A 0.2 M soln of the title compound (264 mg, 0.8 mmol) from Example 98 inDMF stirred at 0° C. was treated with three equal portions ofN-iodosuccinimide (187 mg, 84 mmol). After 15 min, the icebath wasremoved and the mixture was stirred at room temp for 2 hr. The rxnmixture was treated with 10% sodium thiosulfate (aq) (5 mL) andextracted with EtOAc (20 mL×3). The combined organic layers were washedwith H₂O and brine, dried over MgSO₄, filtered, and concentrated invacuo to afford a crude solid. The resulting solid was purified bysilica gel CC using a gradient of EtOAc (0 to 100%) in DCM to afford thetitle compound (333 mg, 91%) as a white solid. LCMS (M+H)⁺: 460.

Step 3:5-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-1-methyl-3-(1-propan-2-yl-pyrazol-4-yl)oxypyridin-2-one

A mixture of5-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-3-iodo-1-methylpyridin-2-one(91 mg, 0.2 mmol), 1-propan-2-ylpyrazol-4-ol (45 mg, 0.36 mmol), CuI (4mg, 10%), 2,2,6,6-tetramethyl-3,5-heptanedione (8 μL, 0.04 mmol) andK₃PO₄ (85 mg, 0.4 mmol) in DMSO (1 mL) was purged with N₂ for 10 min,capped, and heated to 110° C. for 13 hr. After the mixture was filteredthrough a short bed of celite, the filtrate was concentrated in vacuoand purified by prep-HPLC to afford the title compound (36 mg, 40%) as awhite solid. ¹H NMR (400 MHz, DMSO-d₆): δ ppm 0.18-0.26 (m, 2H)0.44-0.53 (m, 2H) 1.03-1.10 (m, 1H) 1.37-1.43 (m, 6H) 3.17-3.21 (m, 3H)3.54-3.61 (m, 3H) 3.87-3.93 (m, 2H) 4.33-4.46 (m, 1H) 7.20-7.25 (m, 1H)7.25-7.28 (m, 1H) 7.33-7.36 (m, 1H) 7.70-7.74 (m, 1H) 7.76-7.85 (m, 4H).LCMS (M+H)⁺: 458.

Example 295:5-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-1-methyl-3-phenoxypyridin-2-one

The title compound was prepared in a manner similar to Step 3 of Example294, substituting phenol for 1-propan-2-ylpyrazol-4-ol. ¹H NMR (400 MHz,DMSO-d₆): δ ppm 0.23-0.30 (m, 2H) 0.41-0.50 (m, 2H) 1.05-1.16 (m, 1H)3.17-3.22 (m, 3H) 3.54-3.61 (m, 3H) 3.88-3.97 (m, 2H) 6.95-7.01 (m, 2H)7.04-7.11 (m, 1H) 7.21-7.27 (m, 1H) 7.30-7.37 (m, 2H) 7.49-7.54 (m, 1H)7.77-7.83 (m, 1H) 7.83-7.92 (m, 2H). LCMS (M+H)⁺: 426.

Example 296:N-[4-(1-butyl-5-methyl-6-oxopyridin-3-yl)-5-(2,4-difluorophenoxy)pyrimidin-2-yl]methanesulfonamide

The title compound was prepared in four steps in a similar manner toExample 248 except that 1-iodobutane was substituted forbromomethylcyclopropane in step 1. ¹H NMR (CDCl₃, 400 MHz): δ 8.95 (s,1H), 8.40 (s, 1H), 8.17 (s, 1H), 8.09 (s, 1H), 7.04-6.95 (m, 2H),6.90-6.88 (m, 1H), 4.01 (t, J=6.8 Hz, 2H), 3.45 (s, 3H), 2.22 (s, 3H),1.75-1.72 (m, 2H), 1.39-1.33 (m, 2H), 0.93 (t, J=7.2 Hz, 3H). LCMS:465.1 (M+H)⁺.

Example 297:N-[4-(1-butyl-5-methyl-6-oxopyridin-3-yl)-5-(2,4-difluorophenoxy)pyrimidin-2-yl]ethanesulfonamide

The title compound was prepared in four steps in a similar manner toExample 248 except that 1-iodobutane was substituted forbromomethylcyclopropane in step 1 and EtSO₂NH₂ was substituted forMeSO₂NH₂ in step 4. ¹H NMR (CDCl₃, 400 MHz): δ 8.83 (s, 1H), 8.38 (s,1H), 8.16 (s, 1H), 8.08 (s, 1H), 7.04-6.95 (m, 2H), 6.94-6.88 (m, 1H),4.00 (t, J=7.2 Hz, 2H), 3.64 (q, J=7.2 Hz, 2H), 2.21 (s, 3H), 1.75-1.72(m, 2H), 1.45 (t, J=7.2 Hz, 3H), 1.37-1.33 (m, 2H), 0.93 (t, J=7.2 Hz,3H). LCMS: 479.1 (M+H)⁺.

Example 298:N-[4-[1-(cyclobutylmethyl)-5-methyl-6-oxopyridin-3-yl]-5-(2,4-difluorophenoxy)pyrimidin-2-yl]methanesulfonamide

The title compound was prepared in four steps in a similar manner toExample 248 except that 1-(bromomethyl)cyclobutane was substituted forbromomethylcyclopropane in step 1. ¹H NMR (CDCl₃, 400 MHz): δ 8.96 (s,1H), 8.39 (s, 1H), 8.14 (s, 1H), 8.09 (s, 1H), 7.02-6.96 (m, 2H),6.91-6.89 (m, 1H), 4.03 (d, J=7.2 Hz, 2H), 3.44 (s, 3H), 2.82-2.74 (m,1H), 2.21 (s, 3H), 2.04-2.03 (m, 2H), 1.89-1.85 (m, 2H), 1.79-1.74 (m,2H). LCMS: 477.1 (M+H)⁺.

Example 299:N-[4-[1-(cyclobutylmethyl)-5-methyl-6-oxopyridin-3-yl]-5-(2,4-difluorophenoxy)pyrimidin-2-yl]ethanesulfonamide

The title compound was prepared in four steps in a similar manner toExample 248 except that 1-(bromomethyl)cyclobutane was substituted forbromomethylcyclopropane in step 1 and EtSO₂NH₂ was substituted forMeSO₂NH₂ in step 4. ¹H NMR (CDCl₃, 400 MHz): δ 8.38 (d, J=2.4 Hz, 1H),8.13 (s, 1H), 8.08 (s, 1H), 7.04-6.98 (m, 2H), 6.97-6.88 (m, 1H), 4.02(d, J=7.2 Hz, 2H), 3.63 (q, J=7.2 Hz, 2H), 2.80-2.76 (m, 1H), 2.20 (s,3H), 2.04-2.03 (m, 2H), 1.89-1.76 (m, 4H), 1.44 (t, J=7.2 Hz, 3H). LCMS:491.1 (M+H)⁺.

Example 300:N-[5-ethyl-4-(2-methyl-1-oxoisoquinolin-4-yl)pyrimidin-2-yl]ethanesulfonamideStep 1

4-chloro-5-ethyl-2-methylsulfonylpyrimidine was prepared in a mannersimilar to Example 152, steps 2-4 except that ethyl butanoate wassubstituted for ethyl 2-(cyclopropylmeth-oxy)acetate in step 2. Thusprepared, 4-chloro-5-ethyl-2-methylsulfonylpyrimidine and the titlecompound of Example 89, step 1 were reacted in a similar manner asExample 152, step 5. Silica gel chromatography (PE:EA=1:1˜0:1) gave thetitle compound (120 mg, yield: 77%) as a yellow solid. ¹H NMR (CDCl₃,400 MHz): δ 8.90 (s, 1H), 8.55 (d, J=8 Hz, 1H), 7.64-7.55 (m, 2H), 7.28(s, 1H), 7.07 (d, J=8 Hz, 1H), 3.69 (s, 3H), 3.39 (s, 3H), 2.67 (q, J=8Hz, 2H), 1.17 (t, J=8 Hz, 3H). LCMS: 344.0 (M+1)⁺.

Step 2:N-[5-ethyl-4-(2-methyl-1-oxoisoquinolin-4-yl)pyrimidin-2-yl]ethanesulfonamide

The title compound of step 1 was treated with EtSO₂NH₂ in a mannersimilar to Example 155 to give the title compound. ¹H NMR (CDCl₃, 400MHz): δ 8.59 (s, 1H), 8.53 (d, J=8 Hz, 1H), 7.63 (t, J=8 Hz, 1H), 7.55(t, J=8 Hz, 1H), 7.23 (d, J=12 Hz, 1H), 7.17 (s, 1H), 3.68 (s, 3H), 3.64(t, J=8 Hz, 2H), 2.52 (q, J=8 Hz, 2H), 1.44 (t, J=8 Hz, 3H), 1.09 (t,J=8 Hz, 3H). LCMS: 373.0 (M+1)⁺.

Examples 301, 303-305 in Table 16 were prepared in a similar multi-stepmanner as Example 300, step 1 wherein ethyl pentanoate was converted to4-chloro-2-methylsulfonyl-5-propylpyrimidine and ethyl hexanoate wasconverted to 5-butyl-4-chloro-2-methylsulfonylpyrimidine. Thus prepared,both the 4-chloro-2-methylsulfonyl-5-propylpyrimidine and the5-butyl-4-chloro-2-methylsulfonylpyrimidine were each coupled to thetitle compound of Example 89, step 1 or1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2(1H)-pyridinonein a manner similar to Example 152, step 5 to give the title compounds.Example 302 was prepared from4-chloro-5-ethyl-2-methylsulfonylpyrimidine (described in Example 300,step 1) and1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2(1H)-pyridinonewhich were also reacted in a manner similar to Example 152, step 5.

Example 302 in Table 16 was prepared from4-chloro-5-ethyl-2-methylsulfonylpyrimidine (described in Example 300,step 1) and1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2(1H)-pyridinonewhich were also reacted in a manner similar to Example 152, step 5.

TABLE 16 Ex. 1H NMR MS No. Structure Name (ppm (δ), 400 MHz) (M + H) 301

2-methyl-4-(2-methylsulfonyl- 5-propylpyrimidin-4-yl) isoquinolin-1-one(CDCl₃, 400 MHz) δ 8.88 (s, 1H), 8.54 (d, J = 8 Hz, 1H), 7.65-7.55 (m,2H), 7.06 (d, J = 8 Hz, 1H), 3.69 (s, 3H), 3.39 (s, 3H), 2.61 (t, J = 8Hz, 2H), 1.56-1.50 (m, 2H), 0.83 (t, J = 7.6 Hz, 3H). 358 302

5-(5-ethyl-2- methylsulfonylpyrimidin-4-yl)- 1,3-dimethylpyridin-2-one(CDCl₃, 400 MHz) δ 8.73 (s, 1 H), 7.84 (s, 1 H), 7.55 (s, 1 H), 3.67 (s,3 H), 3.37 (s, 3 H), 2.90 (q, J = 7.6 Hz, 2 H), 2.23 (s, 3 H), 1.33 (t,J = 7.6 Hz, 3 H) 308 303

1,3-dimethyl-5- (2-methylsulfonyl- 5-propylpyrimidin-4-yl)pyridine-2-one 322 304

4-(5-butyl-2-methylsulfonyl- pyrimidin-4-yl)-2- methylisoquinolin-1-one372 305

5-(5-butyl-2- methylsulfonylpyrimidin-4-yl)- 1,3-dimethylpyridin-2-one(CDCl3, 400 MHz) δ 8.70 (s, 1H), 7.84 (s, 1H), 7.55 (s, 1H), 3.67 (s,3H), 3.37 (s, 3H), 2.84 (t, J = 8.0 Hz, 2H), 2.24 (s, 3H), 1.68 (m, 2H,overlapped with H₂O peak), 1.41 (m, 2H), 0.96 (t, J = 7.2 Hz, 3H). 336

Examples 306-310 in Table 17 were prepared in a similar manner asExample 300, step 2 wherein Examples 301-305 were each treated withEtSO₂NH₂ to give the title compound.

TABLE 17 Prepared Ex. ¹H NMR MS from No. Structure Name (ppm (δ), 400MHz) (M + H) Ex. No. 306

N-[4-(2-methyl-1- oxoisoquinolin-4-yl)-5- propylpyrimidin-2-yl]ethanesulfonamide (CDCl₃, 400 MHz) δ 8.58 (s, 1H), 8.54 (d, J = 8 Hz,1H), 7.64 (t, J = 8 Hz, 1H), 7.56 (t, J = 8 Hz, 1H), 7.24 (s, 1H), 7.18(s, 1H), 3.69 (s, 3H), 3.67-3.61 (m, 2H), 2.47 (t, J = 8 Hz, 2H), 1.51-1.47 (t, J = 8 Hz, 2H), 1.45- 1.41 (t, J = 8 Hz, 3H), 0.81 (t, J = 8 Hz,3H). 387 301 307

N-[4-(1,5-dimethyl-6- oxopyridin-3-yl)-5- ethylpyrimidin-2-yl]ethanesulfonamide (CDCl3, 400 MHz) δ 8.47 (s, 1H), 7.69 (s, 1H), 7.55(s, 1H), 3.67 (m, 5H), 2.75 (q, J = 8 Hz, 2H), 2.24 (s, 3H), 1.45 (t, J= 8 Hz, 3H), 1.26 (t, J = 8 Hz, 3H) 337 302 308

N-[4-(1,5-dimethyl-6- oxopyridin-3-yl)-5- propylpyrimidin-2-yl]ethanesulfonamide (CDCl3, 400 MHz) δ 8.42 (s, 1H), 7.67 (d, J = 2 Hz,1H), 7.53 (s, 1H), 3.69 (t, J = 8 Hz, 2H), 3.65 (d, J = 8 Hz, 3H), 2.66(q, J = 8 Hz, 2H), 2.23 (s, 3H), 1.62- 1.60 (m, 2H), 1.45 (t, J = 8 Hz,3H), 0.98 (t, J = 8 Hz, 3H) 351 303 309

N-[5-butyl-4-(2-methyl- 1-oxoisoquinolin- 4-yl)pyrimidin-2-yl]ethanesulfonamide (CDC13, 400 MHz) δ 8.57 (s, 1H), 8.53 (d, J = 8 Hz,1H), 7.65-7.61 (m, 1H), 7.58-7.53 (m, 1H), 7.24 (d, J = 8 Hz, 1H), 7.17(s, 1H), 3.68 (s, 3H), 3.67-3.61 (m, 2H), 2.48 (t, J = 8 Hz, 2H),1.46-1.39 (m, 5H), 1.23- 1.16 (m, 2H), 0.76 (t, J = 7.2 Hz, 3H) 401 304310

N-[5-butyl-4-(1,5- dimethyl-6-oxopyridin- 3-yl)pyrimidin-2-yl]ethanesulfonamide (CDCl3, 400 MHz) δ 8.47 (s, 1H), 7.71 (s, 1H), 7.55(s, 1H), 3.68-3.62 (m, 5H), 2.69 (t, J = 8 Hz, 2H), 2.23 (s, 3H),1.55-1.46 (m, 2H), 1.40-1.37 (m, 5H), 0.94 (t, J = 7.2 Hz, 3H) 365 305

Example 311:4-[5-(cyclopropylmethoxy)-2-methylsulfonylpyrimidin-4-yl]-2-methylisoquinolin-1-one

The title compound of Example 152, step 5 was purified by preparativeHPLC to give a cream colored powder. ¹H NMR (CDCl₃, 400 MHz): δ 8.53 (s,2H), 7.67-7.63 (m, 2H), 7.57-7.52 (m, 2H), 4.06 (d, J=6.8 Hz, 1H), 3.71(s, 3H), 3.37 (s, 3H), 1.17 (m, 1H), 0.61 (m, 2H), 0.30 (m, 2H). LCMS:386.1 (M+1)⁺.

Example 312: 5-(2-ethyl-5-methylsulfonylphenyl)-1-methylpyridin-2-oneStep 1: 1-ethyl-4-methylsulfonyl-2-nitrobenzene

Bromo-4-methylsulfonyl-2-nitrobenzene (2 g, 7.0 mmol), ethylboronic acid(0.57 g, 7.7 mmol), K₂CO₃ (3.0 g, 21 mmol), Pd(dppf)Cl₂ (0.29 g, 0.35mmol) in 1,4-dioxane/H₂O (4:1) (24 mL) were heated at 85° C. under N₂overnight. Silica gel chromatography (PE:EA=6:1) gave the title compound(0.66 g, 40%) as a brown solid.

Step 2: 2-ethyl-5-methylsulfonylaniline

The title compound of step 1 (0.6 g, 2.6 mmol) and palladium on carbon(0.18 g) in CH₃OH (20 mL) was hydrogenated at 1 atm. for 6 hr. Silicagel chromatography (PE:EA=6:1) gave the title compound (0.49 g, 94%) asa brown liquid.

Step 3: 1-ethyl-2-iodo-4-methylsulfonylbenzene

To the title compound of step 2 (155 mg, 0.8 mmol) in 5M HCl (3 mL) andH₂O (4 mL), cooled to 0° C., was added NaNO₂ (66 mg, 0.96 mmol). Afterstirring 0° C. for 30 min, KI (1.33 g, 8 mmol) in H₂O (2 mL) was addedand the mixture was warmed to room temp and stirred 1 hr. Silica gelchromatography (PE:EA=3:1) gave the title compound (213 mg, 86%) as abrown solid.

Step 4: 5-(2-ethyl-5-methylsulfonylphenyl)-1-methylpyridin-2-one

The title compound of step 3 (62 mg, 0.2 mmol),1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one(57 mg, 0.24 mmol), K₂CO₃ (82 mg, 0.6 mmol), Pd(dppf)Cl₂ (6.2 mg) in1,4-dioxane/H₂O (4:1) (5 mL) were heated at 85° C. under N₂ overnight.Silica gel chromatography (PE:EA=1:1) gave the title compound (56.6 mg,97%) as a brown oil. ¹H NMR (300 MHz, CDCl₃): δ 1.66 (3H, t, J=6.0 Hz),2.63-2.71 (2H, m), 3.05 (3H, s), 3.60 (3H, s), 6.64 (1H, d, J=9.0 Hz),7.28-7.33 (2H, m), 7.48 (1H, d, J=9.0 Hz), 7.70 (1H, s), 7.82-7.85 (1H,m). LCMS: 292 (M+1)⁺.

Example 313: 1-methyl-5-(5-methylsulfonyl-2-propylphenyl)pyridin-2-one

The title compound was prepared in four steps in a similar manner toExample 312, steps 1-4 except that propylboronic acid was substitutedfor ethylboronic acid in step 1. ¹H NMR (CDCl₃, 400 MHz): δ 7.91 (d,J=6.8 Hz, 1H), 7.77 (d, J=15.2 Hz, 2H), 7.62-7.58 (m, 2H), 6.66 (d,J=8.4 Hz, 1H), 3.67 (s, 3H), 3.16 (s, 3H), 2.74-2.78 (m, 2H), 1.63-1.58(m, 2H), 0.93-0.90 (m, 3H). LCMS: 306 (M+1)⁺.

Example 314:2-methyl-4-(5-methylsulfonyl-2-propylphenyl)isoquinolin-1-one

The title compound was prepared in four steps in a similar manner toExample 312, steps 1-4, except that propylboronic acid was substitutedfor ethylboronic acid in step 1 and the title compound of Example 89,step 1 was substituted for1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one instep 4. ¹H NMR (CD₃OD, 400 MHz): δ 8.67 (d, J=8.0 Hz, 1H), 8.20 (dd,J₁=1.6 Hz, J₂=2.4 Hz, 1H), 7.84 (s, 1H), 7.71-7.67 (m, 2H), 7.63-7.59(m, 1H), 7.42 (s, 1H), 7.08 (d, J=8.8 Hz, 1H), 3.71 (s, 3H), 3.18 (m,3H), 2.64-2.57 (m, 1H), 2.51-2.44 (m, 1H), 1.59-1.50 (m, 2H), 0.82-0.78(m, 3H).). LCMS: 356 (M+1)⁺.

Example 315:5-[2-(2-cyclopropylethyl)-5-methylsulfonylphenyl]-1-methylpyridin-2-oneStep 1: 2-(2-cyclopropylethynyl)-5-methylsulfonylaniline

Bromo-4-methylsulfonyl-2-nitrobenzene (1.5 g, 5.36 mmol),ethynylcyclopropane (0.7 g, 10.72 mmol), K₂CO₃ (1.5 g, 10.72 mmol) inCH₃CN (30 ml), Pd(ACN)₂Cl₂ (55.5 mg, 0.21 mmol) and X-phos (128 mg, 0.27mmol) under N₂ were heated at 45° C. for 3 hr. EA extractive work-up andpreparative TLC (PE:EtOAc=5:1) gave the title compound (1.2 g).

Step 2: 2-(2-cyclopropylethyl)-5-methylsulfonylaniline

The title compound of step 1 (1.2 g) was hydrogenated in MeOH (45 mL) ina manner similar to Example 312, step 2. Preparative HPLC gave the titlecompound (422 mg, 41%). ¹H NMR (CDCl₃, 400 MHz): δ 7.19-7.13 (m, 3H),2.95 (s, 3H), 2.60-2.56 (m, 2H), 1.50-1.44 (m, 2H) 0.68-0.65 (m, 1H),0.43-0.38 (m, 2H), 0.03-0.01 (m, 2H).

Step 3: 1-(2-cyclopropylethyl)-2-iodo-4-methylsulfonylbenzene

The title compound of step 2 (442 mg, 1.85 mmol) in 5M HCl (10 mL) wastreated with NaNO₂ (167 mg, 2.41 mmol) followed by KI (3.07 g, 18.50mmol) in H₂O (8 ml) in a manner similar to Example 312, step 3. EAextractive work-up and silica gel chromatography (PE:EA=10:1) gave thetitle compound (600 mg, 93%). ¹H NMR (CDCl₃, 400 MHz): δ 8.27 (d, J=1.6Hz, 1H), 7.74 (dd, J₁=1.6 Hz, J₂=6.4 Hz, 1H), 7.32 (d, J=7.6 Hz, 1H),2.98 (s, 3H), 2.86-2.82 (m, 2H), 1.47-1.41 (m, 2H), 0.69-0.64 (m, 1H),1.42-0.37 (m, 2H), 0.04-0.01 (m, 2H).

Step 4:5-[2-(2-cyclopropylethyl)-5-methylsulfonylphenyl]-1-methylpyridin-2-one

The title compound of step 3 (120 mg, 0.34 mmol),1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one(89 mg, 0.37 mmol), Na2CO3 (72 mg, 0.68 mmol) and Pd(dppf)Cl₂ (15 mg) inDMF/H₂O (6 ml/1.5 ml) under N₂ were heated at 100° C. for 1 hr. EAextractive work-up and preparative TLC (PE:EtOAc=0:1) gave the titlecompound (62 mg, 55%). ¹H NMR (CD₃OD, 400 MHz): δ 7.92 (dd, J₁=2.4 Hz,J₂=5.6 Hz, 1H), 7.81 (d, J=2 Hz, 1H), 7.78 (d, J=2.4 Hz, 1H), 7.65-7.61(m, 2H), 6.69 (m, J=9.2 Hz, 1H), 3.69 (s, 3H), 3.17 (s, 3H), 2.89-2.86(m, 2H), 1.51-1.45 (m, 2H), 0.68-0.65 (m, 1H), 0.45-0.40 (m, 2H),0.04-0.00 (m, 2H). LCMS: 332 (M+1)⁺.

Example 316:4-(2-ethyl-5-methylsulfonylphenyl)-2-methylisoquinolin-1-one

The title compound of Example 312, step 3 was reacted with the titlecompound of Example 89, step 1 in a manner similar to Example 312, step4 to give the title compound. ¹H NMR (400 MHz, CDCl₃): δ 1.10 (3H, t,J=8.0 Hz), 2.51-2.56 (2H, m), 3.10 (3H, s), 3.67 (3H, s), 6.97-7.02 (2H,m), 7.52-7.59 (3H, m), 7.80 (1H, s), 7.97 (1H, d, J=8.0 Hz), 8.54 (1H,d, J=8.0 Hz). LCMS: 342 (M+1)⁺.

Example 317: 5-(2-butyl-5-methylsulfonylphenyl)-1-methylpyridin-2-one

The title compound was prepared in four steps in a similar manner toExample 312, steps 1-4, except that butylboronic acid was substitutedfor ethylboronic acid in step 1. ¹H NMR (400 MHz, MeOH-d₄): δ 0.89 (3H,t, J=8.0 Hz), 1.28-1.35 (2H, m), 1.54-1.58 (2H, m), 2.73-2.77 (2H, m),3.16 (3H, s), 3.67 (3H, s), 6.67 (1H, d, J=4.0 Hz), 7.58-7.62 (2H, m),7.78 (2H, d, J=12.0 Hz), 7.89-7.92 (1H, m). LCMS: 320 (M+1)⁺.

Example 318:4-(2-butyl-5-methylsulfonylphenyl)-2-methylisoquinolin-1-one

The title compound was prepared in four steps in a similar manner toExample 312, steps 1-4, except that butylboronic acid was substitutedfor ethylboronic acid in step 1 and the title compound of Example 89,step 1 was substituted for1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one instep 4. ¹H NMR (300 MHz, MeOH-d₄): δ 0.73 (3H, t, J=7.5 Hz), 1.14-1.21(2H, m), 1.43-1.51 (2H, m), 2.45-2.64 (2H, m), 3.17 (3H, s), 3.70 (3H,s), 7.07 (1H, d, J=9.0 Hz), 7.41 (1H, s), 7.57-7.70 (3H, m), 7.82 (1H,d, J=3.0 Hz), 7.98-8.01 (1H, m), 8.44-8.47 (1H, m). LCMS: 370 (M+1)⁺.

Example 319:4-[2-(2-cyclopropylethyl)-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one

The title compound of Example 315, step 3 was reacted with the titlecompound of Example 89, step 1 in a manner similar to Example 315, step4 to give the title compound. ¹H NMR (CD₃OD, 400 MHz): δ 8.67 (d, J=8.0Hz, 1H), 8.21 (dd, J₁=2.0 Hz, J₂=6.0 Hz, 1H), 8.03 (d, J=2.0 Hz, 1H),7.92-7.86 (m, 2H), 7.82-7.79 (m, 1H), 7.61 (s, 1H), 7.28 (d, J=8.0 Hz,1H), 3.91 (s, 3H), 3.38 (s, 3H), 2.94-2.89 (m, 1H), 2.83-2.77 (m, 1H),1.64-1.55 (m, 2H), 0.75-0.71 (m, 1H), 0.51-0.47 (m, 2H), 0.01-0.00 (m,2H). LCMS: 382 (M+1)⁺.

Example 320:N-[6-(cyclopropylmethoxy)-5-(2-methyl-1-oxoisoquinolin-4-yl)pyridin-3-yl]ethanesulfonamide

A mixture ofN-[5-bromo-6-(cyclopropylmethoxy)pyridin-3-yl]ethanesulfonamide (60 mg,0.21 mmol),2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1-one(77 mg, 0.23 mmol), Pd₂(dba)₃ (7 mg), XPhos (7 mg), and K₃PO₄ (111 mg,0.51 mmol) in dioxane (1.2 mL) and H₂O (140 uL) was purged with N₂,capped, and heated to 70° C. for 2 hr. After the mixture was filteredthrough a short bed of celite, the filtrate was concentrated in vacuoand purified by prep-HPLC to afford the title compound (45 mg, 52%) as awhite solid. ¹H NMR (400 MHz, DMSO-d₆): δ ppm 0.09-0.15 (m, 2H)0.29-0.40 (m, 2H) 0.97-1.08 (m, 1H) 1.20-1.28 (m, 3H) 3.07-3.16 (m, 2H)3.56 (s, 3H) 4.02-4.18 (m, 2H) 7.17-7.22 (m, 1H) 7.52 (s, 3H) 7.62-7.69(m, 1H) 8.06-8.11 (m, 1H) 8.27-8.33 (m, 1H) 9.47-10.31 (m, 1H). LCMS(M+H)⁺: 414.

Example 321:4-[2-(cyclopropylmethoxy)-5-methylsulfonylpyridin-3-yl]-2-methylisoquinolin-1-oneStep 1: 3-bromo-2-chloro-5-methylsulfonylpyridine

A 0.5 M soln of 5-bromo-6-chloropyridine-3-sulfonyl chloride (1.5 g, 5.2mmol) in THF was added dropwise to a mixture of NaHCO₃ (521 mg) andsodium sulfite (847 mg) stirred at room temp in H₂O (15 mL). The rxnmixture was heated to 70° C. for 2 hr. After cooling to room temp, therxn mixture was treated with iodomethane (1.5 mL, 23 mmol) and thenheated to 50° C. for 12 hr. The rxn mixture was extracted with EtOAc (20ml×3); the combined organic layers were washed with H₂O, brine, driedover MgSO4, filtered, and concentrated in vacuo. The resulting solid waspurified by silica gel CC (20% EtOAc in hexanes) to afford the titlecompound (952 mg, 68%). LCMS (M+H)⁺: 271.

Step 2: 3-bromo-2-(cyclopropylmethoxy)-5-methylsulfonylpyridine

A soln of cyclopropylmethanol (146 μL, 1.8 mmol) stirred in DMF (3 mL)at 0° C. was treated with NaH (75 mg, 1.9 mmol, 60% in mineral oil).After stirring at 0° C. for 30 min, the rxn mixture was treated with asoln of 3-bromo-2-chloro-5-methylsulfonylpyridine (400 mg, 1.5 mmol) inDMF (3 mL) by dropwise addition. After the icebath was removed, themixture was stirred at room temp for 14 hr. The rxn mixture was treatedwith H₂O and extracted with EtOAc (30 mL×2). The combined organic layerswere washed with brine, dried over Na₂SO₄, filtered, and concentrated invacuo. The resulting residue was purified by silica gel CC using agradient of EtOAc (5 to 85%) in hexanes to give the title compound (298mg, 65%). LCMS: (M+H)⁺307.

Step 3:4-[2-(cyclopropylmethoxy)-5-methylsulfonylpyridin-3-yl]-2-methylisoquinolin-1-one

A mixture of 3-bromo-2-(cyclopropylmethoxy)-5-methylsulfonylpyridine (67mg, 0.22 mmol),2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1-one(60 mg, 0.21 mmol), Pd₂(dba)₃ (6 mg), X-Phos (7 mg), and K₃PO₄ (111 mg,0.51 mmol) in dioxane (1.2 mL) and H₂O (140 μL) was purged with N₂,capped, and heated at 70° C. for 2 hr. After the mixture was filteredthrough a short bed of celite, the filtrate was concentrated in vacuoand purified by prep-HPLC to afford the title compound (58 mg, 73%) as awhite solid. ¹H NMR (400 MHz, DMSO-d₆): δ ppm 0.12-0.26 (m, 2H)0.28-0.47 (m, 2H) 1.02-1.15 (m, 1H) 3.30-3.32 (m, 3H) 3.54-3.62 (m, 3H)4.02-4.41 (m, 2H) 7.17-7.27 (m, 1H) 7.52-7.59 (m, 1H) 7.60-7.64 (m, 1H)7.64-7.71 (m, 1H) 8.16-8.22 (m, 1H) 8.26-8.35 (m, 1H) 8.70-8.79 (m, 1H).LCMS (M+H)⁺: 385.

Example 322:4-[2-(cyclopropylmethoxy)-5-ethylsulfonylpyridin-3-yl]-2-methylisoquinolin-1-one

The title compound was prepared in a manner similar to Example 321,substituting iodoethane for iodomethane in Step 1. ¹H NMR (400 MHz,DMSO-d₆): δ ppm 0.09-0.15 (m, 2H) 0.31-0.40 (m, 2H) 0.98-1.07 (m, 1H)1.20-1.28 (m, 3H) 3.07-3.17 (m, 2H) 3.54-3.58 (m, 3H) 3.99-4.16 (m, 2H)7.16-7.23 (m, 1H) 7.50-7.59 (m, 3H) 7.63-7.70 (m, 1H) 8.06-8.11 (m, 1H)8.27-8.32 (m, 1H) 9.40-10.08 (m, 1H). LCMS (M+H)⁺: 399.

Example 323:5-[3-[(4-methoxyphenyl)methoxy]-5-methylsulfonylphenyl]-1,3-dimethylpyridin-2-one

A mixture of1-bromo-3-[(4-methoxyphenyl)methoxy]-5-methylsulfonylbenzene (450 mg,1.2 mmol),1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one(300 mg, 1.2 mmol), Pd(dppf)Cl₂ (88 mg) and K₃PO₄ (654 mg, 3 mmol) indioxane (8 mL) and H₂O (800 μL) was purged with N₂ for 7 min, capped,and heated to 75° C. for 1 hr. After the mixture was filtered through ashort bed of celite, the filtrate was concentrated in vacuo and purifiedby silica gel CC using a gradient of EtOAc (5 to 100%) in DCM to affordthe title compound (416 mg, 83%) as a tan solid. ¹H NMR (400 MHz,DMSO-d₆): δ ppm 2.05-2.14 (s, 3H) 3.25-3.28 (s, 3H) 3.49-3.57 (s, 3H)3.74-3.81 (s, 3H) 5.12-5.22 (s, 2H) 6.93-7.03 (m, 2H) 7.34-7.47 (m, 3H)7.52-7.59 (m, 1H) 7.64-7.72 (m, 1H) 7.82-7.90 (m, 1H) 8.14-8.22 (m, 1H).LCMS (M+H)⁺: 414.

Example 324:1,3-dimethyl-5-(3-methylsulfonyl-5-phenylmethoxyphenyl)pyridin-2-oneStep 1: 5-(3-hydroxy-5-methylsulfonylphenyl)-1,3-dimethylpyridin-2-one

A soln of5-[3-[(4-methoxyphenyl)methoxy]-5-methylsulfonylphenyl]-1,3-dimethylpyridin-2-one(410 mg, 1 mmol) in AcOH (10 mL) was heated to 100° C. for 8 hr. Aftercooling to room temp, the rxn mixture was evaporated to dryness invacuo. The resulting residue was diluted with H₂O and extracted withEtOAc (50 ml×3); the combined organic layers were washed with brine,dried over MgSO₄, filtered, and concentrated in vacuo. The resultingsolid was suspensed in ethyl ether, sonicated for 3 min, and filtered.The filter cake was collected to afford the title compound (290 mg, 68%)as a gray solid. LCMS (M+H)⁺: 294.

Step 2:1,3-dimethyl-5-(3-methylsulfonyl-5-phenylmethoxyphenyl)pyridin-2-one

A capped mixture of5-(3-hydroxy-5-methylsulfonylphenyl)-1,3-dimethylpyridin-2-one (25 mg,0.085 mmol), benzyl bromide (20 mg, 0.12 mmol), and Na₂CO₃ (18 mg, 0.17mmol) in DMF (600 μL) was heated to 80° C. for 90 min. The mixture wasfiltered and the filter cake was washed with ACN (500 μL), the filtratewas purified by prep-HPLC to afford the title compound (8 mg, 25%) as atan solid. ¹H NMR (400 MHz, DMSO-d₆): δ ppm 2.08-2.13 (m, 3H) 3.26-3.28(m, 3H) 3.51-3.57 (m, 3H) 5.22-5.34 (m, 2H) 7.33-7.47 (m, 4H) 7.48-7.53(m, 2H) 7.54-7.60 (m, 1H) 7.67-7.71 (m, 1H) 7.83-7.88 (m, 1H) 8.17-8.22(m, 1H). LCMS (M+H)⁺: 384.

For Examples 325-340 in Table 18, the title compound of Step 1 inExample 324 was O-alkylated with the appropriate alkyl halide in asimilar manner to Step 2 of Example 324. For Examples 332-340, Cs₂CO₃ issubstituted for Na₂CO₃.

TABLE 18

Ex. MS No. R¹ Name (M + H) 325

5-[3-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-1,3-dimethylpyridin-2-one 348 326

1,3-dimethyl-5-[3-methylsulfonyl-5-(2- phenylethoxy)phenyl]pyridin-2-one398 327

5-[3-(2-cyclopropylethoxy)-5-methylsulfonylphenyl]-1,3-dimethylpyridin-2-one 362 328

1,3-dimethyl-5-[3-methylsulfonyl-5-(2,2,2-trifluoroethoxy)phenyl]pyridin-2-one 376 329

1,3-dimethyl-5-[3-[(3-methyloxetan-3-yl)methoxy]-5-methylsulfonylphenyl]pyridin-2-one 378 330

1,3-dimethyl-5-[3-methylsulfonyl-5-(pyridin-2-ylmethoxy)phenyl]pyridin-2-one 385 331

5-[3-[(2,6-dimethylphenyl)methoxy]-5-methylsulfonylphenyl]-1,3-dimethylpyridin-2-one 412 332

5-[3-[(2-chlorophenyl)methoxy]-5-methylsulfonylphenyl]-1,3-dimethylpyridin-2-one 419 333

5-[3-[[2-(difluoromethoxy)phenyl]methoxy]-5-methylsulfonylphenyl]-1,3-dimethylpyridin-2-one 450 334

2-[[3-(1,5-dimethyl-6-oxopyridin-3-yl)-5-methylsulfonylphenoxy]methyl]benzonitrile 409 335

5-[3-[(2,4-difluorophenyl)methoxy]-5-methylsulfonylphenyl]-1,3-dimethylpyridin-2-one 420 336

1,3-dimethyl-5-[3-methylsulfonyl-5-(1- phenylethoxy)phenyl]pyridin-2-one398 337

5-[3-[(2,3-dichlorophenyl)methoxy]-5-methylsulfonylphenyl]-1,3-dimethylpyridin-2-one 453 338

1,3-dimethyl-5-[3-methylsulfonyl-5-(pyridin-3-ylmethoxy)phenyl]pyridin-2-one 385 339

3-[[3-(1,5-dimethyl-6-oxopyridin-3-yl)-5-methylsulfonylphenoxy]methyl]benzonitrile 409 340

5-(3-but-2-ynoxy-5-methylsulfonylphenyl)-1,3- dimethylpyridin-2-one 346

Example 341:1,3-dimethyl-5-[3-methylsulfonyl-5-[(1R)-1-phenylethoxy]phenyl]pyridin-2-one

A soln of (1S)-1-phenylethan-1-ol (14 mg, 0.11 mmol) in THF (1 mL)stirred at room temp under N₂ was treated with triphenylphosphine (38mg, 0.15 mmol) and5-(3-hydroxy-5-methylsulfonylphenyl)-1,3-dimethylpyridin-2-one (33 mg,0.11 mmol). After 30 min, the rxn mixture was treated with DIAD (29 mg,0.15 mmol). The N₂ inlet was removed and the mixture was stirred (closedsystem) for 18 hr. After the rxn mixture was diluted with EtOAc (10 ml),it was washed with H₂O, satd NaHCO₃ soln (aq), dried over Na2SO4,filtered, and concentrated in vacuo. The crude residue was diluted withACN (1 mL) and was purified by prep-HPLC to afford the title compound(21 mg, 48%) as an off-white solid. ¹H NMR (400 MHz, DMSO-d6): δ ppm1.61 (d. J=6.4, 3 H) 2.08 (s, 3H) 3.20 (s, 3H) 3.52 (s, 3H) 5.70-5.80(q. J=6.4, 1H) 7.23-7.31 (m, 2H) 7.35-7.41 (m, 2H) 7.44-7.51 (m, 3H)7.56-7.63 (m, 1H) 7.73-7.80 (m, 1H) 8.08-8.15 (m, 1H). LCMS (M+H)⁺: 398.

Example 342:N-[3-(2,4-difluorophenoxy)-5-(1,5-dimethyl-6-oxopyridin-3-yl)phenyl]ethanesulfonamideStep 1: 1-(3-bromo-5-nitrophenoxy)-2,4-difluorobenzene

A mixture of 2,4-difluorophenol (286 mg, 2.2 mmol) and1-bromo-3-fluoro-5-nitrobenzene (440 mg, 2 mmol) in DMF (4.5 mL) wastreated with K₂CO₃ (304 mg, 2.2 mmol). The mixture was heated at 100° C.by microwave irradiation (normal) for 5 hr. The resulting suspension wasdiluted with H₂O and extracted with EtOAc (15 mL×3). The combinedorganic layers were washed with 1N NaOH (aq) (15 mL), H₂O (15 mL),brine, dried over MgSO₄, and concentrated in vacuo. The crude solid waspurified by CC using EtOAc (5% to 25%) in hexanes to afford the titlecompound (200 mg, 30%) as a yellow solid. LCMS (M+H)⁺: 339.

Step 2: 3-bromo-5-(2,4-difluorophenoxy)aniline

A mixture of 1-(3-bromo-5-nitrophenoxy)-2,4-difluorobenzene (54 mg, 0.16mmol), ammonium chloride (18 mg, 0.32 mmol), and iron powder (45 mg,0.80 mmol) suspended in THF (300 μL), H₂O (100 μL) and ethanol (300 μL)was heated at 100° C. using microwave irradiation (normal) for 3 hr. Thecrude rxn mixture was filtered through a short plug of celite; thecelite plug was washed with MeOH (˜5 mL). The resulting filtrate wasconcentrated in vacuo. The resulting residue was diluted with EtOAc (50ml) and washed with satd bicarbonate soln (aq), dried over anhydrousmagnesium sulfate, filtered, and concentrated in vacuo. The crude solidwas purified by silica gel CC using a gradient of EtOAc (5 to 20%) inhexanes to afford the title compound (48 mg, 100%) as a yellow solid.LCMS (M+H)⁺: 301.

Step 3: N-[3-bromo-5-(2,4-difluorophenoxy)phenyl]ethanesulfonamide

Ethylsulfonyl chloride (15 μL, 0.16 mmol) was added dropwise to astirred soln of 3-bromo-5-(2,4-difluorophenoxy)aniline (48 mg, 0.16mmol) and pyridine (40 μL, 0.48 mmol) in DCM (320 μL) at 0° C. under N₂.After the mixture was allowed to warm to room temp and stirred for 12hr, it was treated with 1N HCl (1 mL) and extracted with DCM (3×5 mL);the combined organic extracts were washed with satd bicarbonate soln(aq), dried over Na₂SO₄, filtered and concentrated in vacuo. The crudesolid was purified by silica gel CC using a gradient of EtOAc (5 to 60%)in hexanes to afford the title compound (60 mg, 95%) as a tan solid.LCMS (M+H)⁺: 393.

Step 4:N-[4-(2,4-difluorophenoxy)-5-(1,5-dimethyl-6-oxopyridin-3-yl)phenyl]ethanesulfonamide

A mixture of N-[3-bromo-5-(2,4-difluorophenoxy)phenyl]ethanesulfonamide(70 mg, 0.17 mmol),1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one(44 mg, 0.18 mmol), Pd(dppf)Cl₂ (12 mg) and K₃PO₄ (92 mg, 0.42 mmol) indioxane (1 mL) and H₂O (133 μL) was purged with N₂, capped, and heatedto 75° C. for 1 hr. After the mixture was filtered through a short bedof celite, the filtrate was concentrated in vacuo and purified by silicagel CC using a gradient of MeOH (0 to 10%) in DCM to afford the titlecompound (69 mg, 94%) as an off-white solid. ¹H NMR (400 MHz, DMSO-d₆):δ ppm 1.13-1.22 (m, 3H) 2.07 (s, 3H) 3.08-3.20 (m, 2H) 3.50 (s, 3H)6.65-6.70 (m, 1H) 6.92-6.96 (m, 1H) 7.05-7.10 (m, 1H) 7.12-7.19 (m, 1H)7.28-7.37 (m, 1H) 7.47-7.55 (m, 1H) 7.56-7.59 (m, 1H) 7.87-7.95 (m, 1H)9.76-9.94 (m, 1H). LCMS (M+H)⁺: 435.

Example 343:4-[3-[(4-methoxyphenyl)methoxy]-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one

A mixture of1-bromo-3-[(4-methoxyphenyl)methoxy]-5-methylsulfonylbenzene (103 mg,0.28 mmol),2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1-one(79 mg, 0.28 mmol), Pd(dppf)Cl₂ (20 mg) and K₃PO₄ (153 mg, 0.7 mmol) indioxane (1.9 mL) and H₂O (100 μL) was purged with N₂ for 10 min, capped,and heated to 75° C. for 15 hr. After the mixture was filtered through ashort bed of celite, the filtrate was concentrated in vacuo and purifiedby CC using EtOAc (5% to 100%) in DCM to afford the title compound (100mg, 80%) as a tan solid. ¹H NMR (400 MHz, DMSO-d₆): δ ppm 3.30 (s, 3H)3.58 (s, 3H) 3.77 (s, 3H) 5.14-5.28 (m, 2H) 6.88-7.04 (m, 2H) 7.32-7.80(m, 9H) 8.29-8.43 (m, 1H). LCMS (M+H)⁺: 450.

Example 344:2-methyl-4-(3-methylsulfonyl-5-phenylmethoxyphenyl)isoquinolin-1-oneStep 1: 4-(3-hydroxy-5-methylsulfonylphenyl)-2-methylisoquinolin-1-one

The title compound was prepared in a manner similar to Example 324,substituting4-[3-[(4-methoxyphenyl)methoxy]-5-methylsulfonylphenyl]-2-methylisoquinolin-1-onefor5-[3-[(4-methoxyphenyl)methoxy]-5-methylsulfonylphenyl]-1,3-dimethylpyridin-2-onein Step 1. LCMS (M+H)⁺: 330.

Step 2:2-methyl-4-(3-methylsulfonyl-5-phenylmethoxyphenyl)isoquinolin-1-one

A capped mixture of4-(3-hydroxy-5-methylsulfonylphenyl)-2-methylisoquinolin-1-one (25 mg,0.076 mmol), benzyl bromide (20 mg, 0.12 mmol), and Cs₂CO₃ (50 mg, 0.15mmol) in DMF (600 μL) was heated to 80° C. for 3 hr. The mixture wasfiltered and the filter cake was washed with ACN (500 μL), the filtratewas purified by prep-HPLC to afford the title compound (12 mg, 38%) as atan solid. LCMS (M+H)⁺: 420.

Example 345:4-[3-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one

The title compound was prepared in a manner similar to Example 344,substituting cyclopropylmethyl bromide for benzyl bromide in Step 2.LCMS (M+H)⁺: 384.

Example 346:N-[4-(2,4-difluorophenoxy)-6-(1,5-dimethyl-6-oxopyridin-3-yl)pyrimidin-2-yl]ethanesulfonamideStep 1: 5-(2,6-dichloropyrimidin-4-yl)-1,3-dimethylpyridin-2-one

A mixture of 2,4,6-trichloropyrimidine (275 mg, 1.5 mmol),1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one(246 mg, 1 mmol), Pd(OAc)₂ (20 mg), triphenylphosphine (16 mg), and 2MNa₂CO₃ (1 mL, 2 mmol) in THF (6.7 mL) was purged with N₂ for 5 min,capped, and heated to 80° C. for 3 hr. After the mixture was filteredthrough a short bed of celite, the filtrate was concentrated in vacuoand purified by CC using 0% to 100% EtOAc in DCM to afford the titlecompound (150 mg, 55%) as a white solid. LCMS (M+H)⁺: 271.

Step 2:5-[2-chloro-6-(2,4-difluorophenoxy)pyrimidin-4-yl]-1,3-dimethylpyridin-2-oneand5-[6-chloro-2-(2,4-difluorophenoxy)pyrimidin-4-yl]-1,3-dimethylpyridin-2-one

A mixture of 2,4-difluorophenol (25 mg, 0.19 mmol) and5-(2,6-dichloropyrimidin-4-yl)-1,3-dimethylpyridin-2-one (50 mg, 0.19mmol) in DMF (0.5 mL) and THF (0.5 mL) was treated with K₂CO₃ (304 mg,0.23 mmol). The mixture was stirred at room temp for 3 hr. The resultingsuspension was diluted with H₂O and extracted with EtOAc (10 mL×3). Thecombined organic layers were washed with 1N NaOH_((aq)) (5 mL), H₂O (15mL), brine, dried over MgSO₄, and concentrated in vacuo. The crude solidwas purified by silica gel CC using EtOAc (0% to 50%) in DCM to affordan unseparated mixture of regioisomeric title compounds (66 mg, 96%combined) as a white solid. LCMS (M+H)⁺: 364 for both regioisomers.

Step 3:N-[4-(2,4-difluorophenoxy)-6-(1,5-dimethyl-6-oxopyridin-3-yl)pyrimidin-2-yl]ethanesulfonamide

A soln of ethanesulfonamide (80 mg, 0.73 mmol) in DMF (2 mL) was treatedwith NaH (27 mg, 0.68 mmol, 60% by weight). After 15 min, the mixturewas treated with a DMF (1 mL) soln of title compounds obtained from Step2. The rxn mixture was stirred at 50° C. for 14 hr. The resultingsuspension was diluted with H₂O and extracted with EtOAc (10 mL×3). Thecombined organic layers were washed with brine, dried over Na₂SO₄, andconcentrated in vacuo. Preparative HPLC isolated both regioisomers asExamples 346 and 347. The title compound (6 mg, 8%) was obtained as awhite solid. ¹H NMR (400 MHz, DMSO-d₆): δ ppm 1.08 (t, J=7.1 Hz, 3H)2.07 (s, 3H) 3.11 (q, J=7.1 Hz, 2H) 3.54 (s, 3H) 6.81 (s, 1H) 7.17 (m,1H) 7.47 (s, 2H) 7.79 (s, 1H) 8.37 (s, 1H) 11.37 (bs, 1H). LCMS (M+H)⁺:437.

Example 347:N-[2-(2,4-difluorophenoxy)-6-(1,5-dimethyl-6-oxopyridin-3-yl)pyrimidin-4-yl]ethanesulfonamide

The preparative HPLC of Example 346, step 3 also isolated thisregioisomer. The title compound (2 mg, 3%) was obtained as a whitesolid. ¹H NMR (400 MHz, DMSO-d₆): δ ppm 1.06-1.13 (m, 3H) 2.08-2.12 (m,3H) 3.11-3.23 (m, 2H) 3.54-3.57 (m, 3H) 7.14-7.28 (m, 2H) 7.45-7.54 (m,2H) 8.04-8.09 (m, 1H) 8.52-8.57 (m, 1H) 10.92-11.26 (m, 1H), both as awhite solids. LCMS (M+H)⁺: 437.

Example 348:4-[3-[[2-(difluoromethoxy)phenyl]methoxy]-5-methylsulfonylphenyl]-6-methylfuro[2,3-c]pyridin-7-oneStep 1:4-[3-[(4-methoxyphenyl)methoxy]-5-methylsulfonylphenyl]-6-methylfuro[2,3-c]pyridin-7-one

A mixture of1-bromo-3-[(4-methoxyphenyl)methoxy]-5-methylsulfonylbenzene (470 mg,1.27 mmol),6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)furo[2,3-c]pyridin-7-one(316 mg, 1.15 mmol), Pd(dppf)Cl₂ (84 mg) and K₃PO₄ (610 mg, 2.9 mmol) indioxane (7 mL) and H₂O (700 μL) was purged with N₂ for 7 min, capped,and heated to 70° C. for 2 hr and room temp for 48 hr. After the mixturewas diluted with EtOAc (5 mL) and H₂O (5 mL), it was filtered through ashort bed of celite. After the filtrate was separated, the aq layer waswashed with EtOAc (25 mL×3). The combined organic layers were washedwith H₂O and brine, dried over MgSO₄, and concentrated in vacuo. Thecrude solid was purified by CC using EtOAc (0% to 100%) in DCM to affordthe title compound (375 mg, 74%) as a white solid. LCMS (M+H)⁺: 440.

Step 2:4-(3-hydroxy-5-methylsulfonylphenyl)-6-methylfuro[2,3-c]pyridin-7-one

A soln of4-[3-[(4-methoxyphenyl)methoxy]-5-methylsulfonylphenyl]-6-methylfuro[2,3-c]pyridin-7-one(370 mg, 0.84 mmol) in AcOH (6 mL) was heated to 100° C. for 12 hr.After cooling to room temp, the rxn mixture was evaporated to dryness invacuo. The resulting residue was diluted with H₂O and extracted withEtOAc (20 ml×3); the combined organic layers were washed with brine,dried over MgSO4, filtered, and concentrated in vacuo. The resultingsolid was suspended in a 1:1 mixture of EtOAc:hexanes, sonicated for 1min, and filtered. The filter cake was collected to afford the titlecompound (210 mg, 78%) as a gray solid. LCMS (M+H)⁺: 320.

Step 3:4-[3-[[2-(difluoromethoxy)phenyl]methoxy]-5-methylsulfonylphenyl]-6-methylfuro[2,3-c]pyridin-7-one

A capped mixture of4-(3-hydroxy-5-methylsulfonylphenyl)-6-methylfuro[2,3-c]pyridin-7-one(25 mg, 0.08 mmol), 1-(bromomethyl)-2-(difluoromethoxy)benzene (28 mg,0.12 mmol), and Cs₂CO₃ (50 mg, 0.15 mmol) in DMF (900 μL) was heated to80° C. for 3 hr. The mixture was filtered and the filter cake was washedwith ACN (500 μL), the filtrate was purified by prep-HPLC to afford thetitle compound (22 mg, 58%) as a white solid. LCMS (M+H)⁺: 476.

Example 349:6-methyl-4-(3-methylsulfonyl-5-phenylmethoxyphenyl)furo[2,3-c]pyridin-7-one

The title compound was prepared in a manner similar to Example 348,substituting benzyl bromide for1-(bromomethyl)-2-(difluoromethoxy)benzene in Step 2. LCMS (M+H)⁺: 410.

Example 350:4-[3-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-6-methylfuro[2,3-c]pyridine-7-one

The title compound was prepared in a manner similar to Example 348,substituting bromomethylcyclopropane for1-(bromomethyl)-2-(difluoromethoxy)benzene in Step 3. LCMS (M+H)⁺: 374.

Examples 351-356 in Table 19 were prepared in a similar multi-stepmanner as Example 300, step 1, wherein either ethyl pentanoate wasconverted to 4-chloro-2-methylsulfonyl-5-propylpyrimidine or ethylhexanoate was converted to 5-butyl-4-chloro-2-methylsulfonylpyrimidinewhich were then each reacted with (a)3-methoxy-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one(described in Example 146, step 3); (b) the title compound of Example98, step 1; or (c)3-chloro-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one(described in Example 134) in a manner similar to Example 152, step 5,to give the title compound.

TABLE 19 Chemical Synthesis ¹H NMR MS Example Structure Name (ppm (δ),400 MHz) (M + H) 351

1-methyl-5-(2- methylsulfonyl-5- propylpyrimidin-4-yl) pyridin-2-one(CDCl₃, 400 MHz) δ 8.72 (s, 1H), 8.00 (s, 1H), 7.67 (q, J = 6.8 Hz, 1H),6.67 (d, J = 9.6 Hz, 1H), 3.68 (s, 3H), 3.38 (s, 3H), 2.82 (t, J = 8.0Hz, 2H), 1.73 (m, 2H), 1.00 (t, J = 7.2 Hz, 3H). 308 352

5-(5-butyl-2-methyl- sulfonylpyrimidin-4-yl)- 1-methylpyridin-2-one 322353

3-chloro-1-methyl-5-(2- methylsulfonyl-5- propylpyrimidin-4-yl)pyridin-2-one 342 354

5-(5-butyl-2-methyl- sulfonylpyrimidin-4-yl)- 3-chloro-1-methyl-pyridin-2-one 356 355

3-methoxy-1-methyl-5- (2-methylsulfonyl-5- propylpyrimidin-4-yl)pyridin-2-one 338 356

5-(5-butyl-2-methyl- sulfonylpyrimidin-4-yl)- 3-methoxy-1-methyl-pyridin-2-one 352

Examples 357-362 in Table 20 were prepared in a similar manner asExample 300, step 2 wherein Examples 351-356 were each treated withEtSO₂NH₂ to give the title compound.

Example 363 in Table 20 was prepared in a similar manner as Example 152,step 6 wherein Example 305 was treated with MeSO₂NH₂ to give the titlecompound.

TABLE 20 Chemical Prepared Synthesis 1H NMR MS from Example StructureName (ppm (δ), 400 MHz) (M + H) Ex. No. 357

N-[4-(1-methyl-6- oxopyridin-3-yl)-5- propylpyrimidin-2-yl]ethanesulfonamide (CDCl₃, 400 MHz) δ 8.45 (s, 1H), 7.84 (s, 1H), 7.68(d, J = 9.6 Hz, 1H), 6.68 (d, J = 9.2 Hz, 1H), 3.68 (s, 3H), 3.64 (t, J= 7.6 Hz, 2H), 2.67 (t, J = 8.0 Hz, 2H), 1.64 (q, J = 7.6 Hz, 2H), 1.45(t, J = 7.2 Hz, 3H), 0.98 (t, J = 7.2 Hz, 3H) 337 351 358

N-[5-butyl-4-(1- methyl-6-oxopyridin- 3-yl)pyrimidin-2-yl]ethanesulfonamide (CDCl₃, 400 MHz) δ 8.44 (s, 1H), 7.84 (s, 1H), 7.69(d, J = 9.6 Hz, 1H), 6.68 (d, J = 9.2 Hz, 1 H), 3.68 (s, 3H), 3.64 (t, J= 7.6 Hz, 2H), 2.68 (t, J = 7.6 Hz, 2H), 1.57 (t, J = 8.0 Hz, 2H), 1.46(d, J = 7.6 Hz, 3H), 1.41 (t, J = 8.4 Hz, 2H), 0.93 (t, J = 7.2 Hz, 3H)351 352 359

N-[4-(5-chloro-1- methyl-6-oxopyridin- 3-yl)-5-propyl- pyrimidin-2-yl]ethanesulfonamide (CDCl₃, 400 MHz) δ 8.47 (s, 1H), 7.87 (d, J = 2.8 Hz,1H), 7.78 (d, J = 2.0 Hz, 1H), 3.72 (s, 3H), 3.65 (q, J = 7.2 Hz, 2H),2.67 (t, J = 8.0 Hz, 2H), 1.65 (d, J = 8.0 Hz, 2H), 1.45 (t, J = 7.2 Hz,3H), 1.00 (t, J = 7.2 Hz, 3H) 371 353 360

N-[5-butyl-4-(5- chloro-1-methyl-6- oxopyridin-3-yl) pyrimidin-2-yl]ethanesulfonamide (CDCl₃, 400 MHz) δ 8.48 (s, 1H), 7.90 (d, J = 2.4 Hz,1H), 7.80 (d, J = 2.4 Hz, 1H), 3.74 (s, 3H), 3.66 (q, J = 7.2 Hz, 2H),2.70 (t, J = 8.0 Hz, 2 H), 1.61 (m, 2H), 1.47 (t, J = 7.2 Hz, 3H), 1.42(q, J = 8.0 Hz, 2H), 1.00 (t, J = 7.2 Hz, 3H) 385 354 361

N-[4-(5-methoxy-1- methyl-6-oxopyridin- 3-yl)-5-propyl- pyrimidin-2-yl]ethanesulfonamide (CDCl₃, 400 MHz) δ 8.46 (s, 1H), 7.40 (d, J = 1.6 Hz,1H), 7.05 (s, 1H), 3.89 (s, 3H), 3.68 (s, 3H), 3.65 (t, J = 8.0 Hz, 2H),2.69 (t, J = 8.0 Hz, 2H), 1.67 (m, 2H), 1.44 (t, J = 7.2 Hz, 3H), 1.00(t, J = 7.2 Hz, 3H) 367 355 362

N-[5-butyl-4-(5- methoxy-1-methyl-6- oxopyridin-3-yl) pyrimidin-2-yl]ethanesulfonamide (CDCl₃, 400 MHz) δ 8.43 (s, 1H), 7.39 (d, J = 2.0 Hz,1H), 7.03 (d, J = 2 Hz, 1H), 3.89 (s, 3H), 3.68 (s, 3H), 3.64 (d, J =8.0 Hz, 2H), 2.71 (t, J = 8.0 Hz, 2H), 1.67 (m, 2H, overlapped with H₂Opeak), 1.45 (t, J = 7.2 Hz, 3H), 1.39 (q, J = 7.2 Hz, 2H), 0.94 (t, J =7.2 Hz, 3H) 381 356 363

N-[5-butyl-4-(1,5- dimethyl-6- oxopyridin-3-yl) pyrimidin-2-yl]methanesulfonamide (CDCl₃, 400 MHz) δ 8.47 (s, 1H), 7.70 (d, J = 2 Hz,1H), 7.55 (s, 1H), 3.66 (s, 3H), 3.46 (s, 3H), 2.69 (t, J = 8.0 Hz, 2H),2.23 (s, 3H), 1.56 (q, J = 8.0 Hz, 2H), 1.38 (q, J = 7.2 Hz, 2H), 0.94(t, J = 7.2 Hz, 3H) 351 305

Example 364:4-[2-(cyclopropylmethoxy)-5-propan-2-ylsulfonylphenyl]-2-methylisoquinolin-1-oneStep 1: 5-bromo-7H-[1,2,4]triazolo[4,3-a]pyrazin-8-one

The title compound was prepared in three steps from3-bromo-4-fluorobenzenethiol in a manner similar to Example 79, steps1-3 except that 2-iodopropane was substituted for ethyl iodide in step 1and the alkoxide of cyclopropylmethanol was substituted for sodiummethoxide in step 3. ¹H NMR (CDCl₃, 400 MHz): δ 8.05 (d, J=2.4 Hz, 1H),7.76 (dd, J₁=2.4 Hz, J₂=8.4, 1H), 6.97 (d, J=8.4 Hz, 1H), 3.18 (m, 1H),1.29 (d, J=6.8 Hz, 6H), 0.86 (m, 1H), 0.71 (d, J=6.8 Hz, 2H), 0.45 (d,J=5.6 Hz, 2H). LCMS (M+H⁺): 333.0; 335.0.

Step 2:4-[2-(cyclopropylmethoxy)-5-propan-2-ylsulfonylphenyl]-2-methylisoquinolin-1-one

The title compound of step 1 was coupled to the title compound ofExample 89, step 1 in a manner similar Example 89, step 2 to give thetitle compound as a white solid. ¹H NMR (CDCl₃, 400 MHz): δ 8.52 (d,J=7.2 Hz, 1H), 7.91 (dd, J₁=6.4 Hz, J₂=8.4, 1H), 7.80 (d, J=2.4 Hz, 1H),7.51-7.57 (m, 2H), 7.15 (d, J=8.0 Hz, 1H), 7.09 (t, J=8.4 Hz, 1H), 3.89(s, 2H), 3.67 (s, 3H), 3.18-3.25 (m, 1H), 1.33 (d, J=6.8 Hz, 6H),0.99-1.02 (m, 1H), 0.414 (m, 2H), 0.11 (s, 2H). LCMS (M+H)⁺: 412.

Example 365:8-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-6-methyl-4H-pyrido[4,3-b][1,4]oxazine-3,5-dioneStep 1: 6-methyl-4H-pyrido[4,3-b][1,4]oxazine-3,5-dione

To a soln of the title compound of Example 237, step 3 (1.6 g, 9.01mmol, 1.00 Eq) in CH₂Cl₂ (150 mL) at 0° C. under N₂ is addedchloroacetyl chloride (0.75 mL, 9 mmol) dropwise. Pyridine (2.2 mL, 37mmol) is then added, and the mixture was stirred for 5 hr at room temp.Satd aq KHSO₄ (100 mL) was added and the aq layer was extracted a totalof three times with CH₂Cl₂. The combined organic layers were dried overNa₂SO₄, filtered, and then acetone (200 mL) followed by cesium carbonate(14.6 g, 45 mmol) were added directly to the filtrate (250 mL). Themixture was then heated at 50° C. for 2 hr. The volume was reduced andH₂O was added. Extractive work-up with 3:1 CH₂Cl₂:isopropanol followedby trituration with 1:2 EA:PE gave the title compound (400 mg, yield:24.67%) as a yellow solid. ¹H NMR (CDCl₃, 400 MHz): δ 8.17-8.14 (br,1H), 7.01 (d, J=7.2 Hz, 1H), 6.07 (d, J=7.2 Hz, 1H), 4.69 (s, 1H), 3.59(s, 3H). LCMS: 181.0 (M+H)⁺.

Step 2: 8-bromo-6-methyl-4H-pyrido[4,3-b][1,4]oxazine-3,5-dione

At room temp, to the title compound of step 1 (90 mg, 0.5 mmol) inanhydrous CH₃CN (1 mL) was added NBS (89 mg, 0.5 mmol). After stirringabout 2 h, additional NBS (75 mg, 0.4 mmol) was added and the rxn wascomplete within 20 min. EA extractive work-up and silica gelchromatography gave the title compound (51 mg, 0.39 mmol) in 39% yield.

Step 3:8-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-6-methyl-4H-pyrido[4,3-b][1,4]oxazine-3,5-dione

The title compound of step 2 was reacted with2-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolanein a manner similar to Example 224, step 5. Silica gel chromatography(40-100% EA in hexane over 8 min) gave the title compound. ¹H NMR(DMSO-d6, 400 MHz): δ ppm 0.27-0.33 (m, 2H) 0.51-0.57 (m, 2H) 1.11 (t,J=7.33 Hz, 3H) 1.14-1.22 (m, 1H, partially obscured) 3.22-3.28 (m, 2H)3.51 (s, 3H) 3.96 (d, J=7.07 Hz, 2H) 4.54 (s, 2H) 7.27 (d, J=8.84 Hz,1H) 7.52 (s, 1H) 7.67 (d, J=2.02 Hz, 1H) 7.79-7.92 (m, 1H) 10.10 (s,1H). LCMS: 419 (M+H)⁺.

Example 366:8-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-6-methyl-3,4,4a,8a-tetrahydro-2H-pyrido[4,3-b][1,4]oxazin-5-one

The title compound of Example 365, step 3, in anhydrous THF was treatedwith excess 1M LAH in THF at room temp. After about 30 min, ice, H₂O,MeOH, and 1M HCl were added followed by satd aq NaHCO₃ and EA extractivework-up. Silica gel chromatography (EA, followed by 5% methanol in EA)gave the title compound as a clear glass. ¹H NMR: (DMSO-d₆, 400 MHz) δppm 0.32 (brs, 2H) 0.54 (brs, 2H) 1.03-1.30 (m, 4H) 3.45 (brs, 3H) 3.94(brs, 2H) 4.09 (brs, 2H) 5.03 (brs, 1H) 7.05 (brs, 1H) 7.22 (brs, 1H)7.62 (brs, 1H) 7.78 (brs, 1H). ¹H NMR: (DMSO-d₆/DCl, 400 MHz) δ ppm 0.29(brs, 2H) 0.55 (brs, 2H) 1.10 (brs, 4H) 3.25 (brs, 2H) 3.45 (brs, 2H)3.51 (brs, 3H) 3.93 (brs, 2H) 4.43 (brs, 2H) 7.27 (brs, 1H) 7.69 (brs,1H) 7.84 (brs, 2H). LCMS: 405 (M+H)⁺.

Example 367:N-[4-(2,4-difluorophenoxy)-3-(7-methyl-8-oxoimidazo[1,5-a]pyrazin-5-yl)phenyl]methanesulfonamide

To a soln of the title compound from Example 129, Step 2 (140 mg, 0.38mmol) in THF (20 ml) was added pyridine (152 mg, 1.90 mmol). Thenmethanesulfonyl chloride (48 mg, 0.46 mmol) was added to the soln at 0°C. The soln was allowed to warm up to room temp and heated to reflux forovernight. The rxn mixture was concentrated under reduced pressure toyield the crude product that was purified by prep-HPLC to give the titlecompound (75.26 mg, 44%) as a yellow solid. ¹H NMR (CDCl₃, 400 MHz): δ8.60 (s, 1H), 8.15 (s, 1H), 7.50 (d, J=2.8 Hz, 1H), 7.30 (dd, J=8.8, 2.4Hz, 1H), 7.18 (td, J=8.8, 5.3 Hz, 1H), 7.00-6.88 (m, 2H), 6.83 (s, 1H),6.78 (d, J=8.8 Hz, 1H), 3.60 (s, 3H), 3.03 (s, 3H). LCMS: 447.0 (M+1)⁺.

Example 368:5-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-7-methylimidazo[1,5-a]pyrazine-8-one

To a microwave vial containing5-bromo-7-methylimidazo[1,5-a]pyrazin-8-one (150 mg, 0.66 mmol),2-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(290 mg, 0.80 mmol) and NaHCO₃ (1 mL, 2M) in dioxane (3 mL) was addedPd(dppf)Cl₂ (80 mg, 0.10 mmol). The mixture was purge with N₂ for 2 minand sealed. The rxn was irradiated in microwave at 100° C. for 2 hr. H₂O(20 mL) was added and the mixture was extracted with EtOAc (20 mL×3).The combined organic layers were washed with brine (20 mL), dried withNa₂SO₄, filtered, and concentrated in vacuum. The residue was purifiedby CC (PE:EA=5:1 to 1:1) to afford the title compound (55.3 mg, 22%) asa light yellow solid. ¹H NMR (CDCl₃, 400 MHz): δ 8.03 (dd, J₁=8.4 Hz,J₂=2.0 Hz, 2H), 7.94 (d, J=2.0 Hz, 1H), 7.56 (s, 1H), 7.15 (d, J=8.8 Hz,1H), 6.49 (s, 1H), 3.96 (d, J=6.4 Hz, 2H), 3.54 (s, 3H), 3.16 (q, J=7.6Hz, 1H), 1.33 (t, J=7.6 Hz, 1H), 1.08 (s, 1H), 0.54 (d, J=7.2 Hz, 2H),0.54 (d, J=4.4 Hz, 2H). LCMS: 388.1 (M+1)⁺.

Example 369:5-[2-(2,4-difluorophenoxy)-5-(ethylsulfonylmethyl)phenyl]-7-methylimidazo[1,5-a]pyrazin-8-oneStep 1:2-[2-(2,4-difluorophenoxy)-5-(ethylsulfonylmethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

A mixture of2-bromo-1-(2,4-difluorophenoxy)-4-(ethylsulfonylmethyl)benzene (250 mg,0.64 mmol), bis(pinacolato)diboron (255 mg, 0.96 mmol), KOAc (189 mg,1.92 mmol) and Pd(dppf)Cl₂ (44 mg, 0.06 mmol) in dioxane (5 mL) wasstirred at 70° C. for 18 hr under N₂. The mixture was concentrated andthe residue was purified by CC to give the title compound (150 mg,53.4%) as yellow solid. LCMS: 439.2 (M+1)⁺.

Step 2:5-[2-(2,4-difluorophenoxy)-5-(ethylsulfonylmethyl)phenyl]-7-methylimidazo[1,5-a]pyrazin-8-one

A mixture of the title compound from Step 1 (150 mg, 0.34 mmol), thetitle compound from Example 129 Step 1 (87 mg, 0.38 mmol), K₃PO₄ (217mg, 1.02 mmol) and Pd(dppf)Cl₂ (22 mg, 0.03 mmol) in dioxane (5 mL) andH₂O (1 mL) was stirred at 70° C. for 18 hr under N₂. The resultingmixture was filtered and concentrated. The residue was purified byprep-HPLC to give the title compound (70.0 mg, 45%) as a yellow solid.¹H NMR (DMSO-d6, 400 MHz): δ 8.83 (s, 1H), 8.33 (s, 1H), 7.64 (d, J=2.0Hz, 1H), 7.57 (dd, J₁=8.8 Hz, J₂=2.0 Hz, 1H), 7.53-7.41 (m, 2H), 7.37(s, 1H), 7.20-7.12 (m, 1H), 6.93 (d, J=8.8 Hz, 1H), 4.54 (s, 2H), 3.45(s, 3H), 3.09 (q, J=7.6 Hz, 2H), 1.23 (t, J=7.6 Hz, 3H). LCMS: 460.1(M+1)⁺.

Example 370:7-methyl-5-[5-(methylsulfonylmethyl)-2-(2,2,2-trifluoroethoxy)phenyl]imidazo[1,5-a]pyrazin-8-oneStep 1:4,4,5,5-tetramethyl-2-[5-(methylsulfonylmethyl)-2-(2,2,2-trifluoroethoxy)phenyl]-1,3,2-dioxaborolane

The title compound was prepared in a manner similar to Example 369, Step1, by substituting2-bromo-4-(methylsulfonylmethyl)-1-(2,2,2-trifluoroethoxy)benzene for2-bromo-1-(2,4-difluorophenoxy)-4-(ethylsulfonylmethyl)benzene. LCMS:395.2 (M+1)⁺.

Step 2:7-methyl-5-[5-(methylsulfonylmethyl)-2-(2,2,2-trifluoroethoxy)phenyl]imidazo[1,5-a]pyrazin-8-one

The title compound was prepared in a manner similar to Example 369, Step2, by substituting4,4,5,5-tetramethyl-2-[5-(methylsulfonylmethyl)-2-(2,2,2-trifluoroethoxy)phenyl]-1,3,2dioxaborolane for2-[2-(2,4-difluorophenoxy)-5-(ethylsulfonylmethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.¹H NMR (DMSO-d₆, 400 MHz): δ 8.64 (s, 1H), 8.32 (s, 1H), 7.64 (dd,J₁=8.8 Hz, J₂=2.0 Hz, 1H), 7.56 (s, 1H), 7.39 (d, J=8.8 Hz, 1H), 7.25(s, 1H), 4.86 (q, J=8.8 Hz, 2H), 4.53 (s, 2H), 3.44 (s, 3H), 2.94 (s,3H). LCMS: 416.1 (M+1)⁺.

Example 371:5-[5-(ethylsulfonylmethyl)-2-(2,2,2-trifluoroethoxy)phenyl]-7-methylimidazo[1,5-a]pyrazin-8-oneStep 1:2-[5-(ethylsulfonylmethyl)-2-(2,2,2-trifluoroethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

The title compound was prepared in a manner similar to Example 369, Step1, by substituting2-bromo-4-(ethylsulfonylmethyl)-1-(2,2,2-trifluoroethoxy)benzene for2-bromo-1-(2,4-difluorophenoxy)-4-(ethylsulfonylmethyl)benzene. LCMS:409.2 (M+1)+.

Step 2:5-[5-(ethylsulfonylmethyl)-2-(2,2,2-trifluoroethoxy)phenyl]-7-methylimidazo[1,5-a]pyrazin-8-one

The title compound was prepared in a manner similar to Example 369, Step2, by substituting2-[5-(ethylsulfonylmethyl)-2-(2,2,2-trifluoroethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolanefor2-[2-(2,4-difluorophenoxy)-5-(ethylsulfonylmethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.¹H NMR (DMSO-d6, 400 MHz) δ 8.99 (s, 1H), 8.47 (s, 1H), 7.61 (d, J=8.8Hz, 1H), 7.52 (s, 1H), 7.35 (d, J=8.8 Hz, 1H), 7.31 (s, 1H), 4.82 (q,J=8.4 Hz, 2H), 4.48 (s, 2H), 3.42 (s, 3H), 3.04 (q, J=7.2 Hz, 2H), 2.94(t, J=7.2 Hz, 3H). LCMS: 430.1 (M+1)⁺.

Example 372:5-[2-(2,4-difluorophenoxy)-5-(methylsulfonylmethyl)phenyl]-7-methylimidazo[1,5-a]pyrazin-8-oneStep 1:2-[2-(2,4-difluorophenoxy)-5-(methylsulfonylmethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

The title compound was prepared in a manner similar to Example 369, Step1, by substituting2-bromo-1-(2,4-difluorophenoxy)-4-(methylsulfonylmethyl)benzene for2-bromo-1-(2,4-difluorophenoxy)-4-(ethylsulfonylmethyl)benzene. LCMS:442.2 (M+18)⁺.

Step 2:5-[2-(2,4-difluorophenoxy)-5-(methylsulfonylmethyl)phenyl]-7-methylimidazo[1,5-a]pyrazin-8-one

The title compound was prepared in a manner similar to Example 369, Step2, by substituting2-[2-(2,4-difluorophenoxy)-5-(methylsulfonylmethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolanefor2-[2-(2,4-difluorophenoxy)-5-(ethylsulfonylmethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.¹H NMR (DMSO-d6, 400 MHz) δ 8.59 (s, 1H), 8.19 (s, 1H), 7.65 (d, J=2.0Hz, 1H), 7.57 (dd, J₁=8.8 Hz, J₂=2.0 Hz, 1H), 7.52-7.39 (m, 2H), 7.30(s, 1H), 7.18-7.11 (m, 1H), 6.94 (d, J=8.8 Hz, 1H), 4.55 (s, 2H), 3.44(s, 3H), 2.96 (s, 3H). LCMS: 446.1 (M+1)⁺.

Example 373:5-[2-(4,4-difluorocyclohexyl)oxy-5-ethylsulfonylphenyl]-7-methylimidazo[1,5-a]pyrazin-8-oneStep 1:2-(5-ethylsulfonyl-2-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

Bromo-4-ethylsulfonyl-1-fluorobenzene (5.00 g, 18.72 mmol), AcOK (3.88g, 56.16 mmol, 3 eq), pinacol ester (9.51 g, 37.44 mmol, 2 eq),Pd₂(dba)₃ (17.14 g, 18.72 mmol, 1 eq) and X-Phos (9.24 g, 18.72 mmol, 1eq) in dioxane (300 mL) was degassed and then heated to 60° C. overnightunder N₂. The rxn mixture was poured into H₂O (300 mL). The mixture wasextracted with EA (3×250 mL). The combined organic phase were washedwith satd brine (300 mL), dried over anhydrous MgSO₄, filtered andconcentrated under reduced pressure to give a residue that was purifiedby silica gel CC to afford the title compound (1.87 g, 32%) as a graysolid. ¹H NMR (CDCl₃, 400 MHz): δ 8.34-8.31 (m, 1H), 8.01-7.98 (m, 1H),7.22 (d, J=8.8 Hz, 1H), 3.14 (q, J=7.6 Hz, 2H), 1.37 (s, 12H), 1.27 (t,J=7.6 Hz, 3H).

Step 2:5-(5-ethylsulfonyl-2-fluorophenyl)-7-methylimidazo[1,5-a]pyrazin-8-one

5-bromo-7-methylimidazo[1,5-a]pyrazin-8-one (600 mg, 2.63 mmol, 0.83Eq), the title compound from Step 2 (1.00 g, 3.18 mmol, 1.00 Eq), K₃PO₄(2.03 g, 9.55 mmol, 3.00 Eq) and Pd(dppf)Cl₂ (118 mg, 0.16 mmol, 0.05Eq) in dioxane (20 mL) was degassed and then heated at 60° C. overnightunder N₂. The rxn mixture was poured into H₂O. The mixture was extractedwith EA (3×25 mL). The organic phase was washed with brine (30 mL),dried over anhydrous MgSO₄, filtered and concentrated under vacuum togive a residue which was purified by silica gel chromatography to affordthe title compound (600 mg, yield: 56.24%). ¹H NMR (CDCl₃, 400 MHz): δ8.50 (s, 1H), 8.17 (s, 1H), 8.12-8.08 (m, 2H), 7.50 (t, J=8.8 Hz, 1H),6.90 (s, 1H), 3.59 (s, 3H), 3.17 (q, J=7.2 Hz, 2H), 0.89-0.83 (m, 3H).

Step 3:5-[2-(4,4-difluorocyclohexyl)oxy-5-ethylsulfonylphenyl]-7-methylimidazo[1,5-a]pyrazin-8-one

To a soln of 4,4-difluorocyclohexan-1-ol (162 mg, 1.19 mmol) in THF (10mL) was added NaH (48 mg, 1.19 mmol, 60% in mineral oil) in one portionat 25° C. under N₂. The mixture was stirred at 25° C. for 30 min. Thenthe title compound from Step 2 (200 mg, 0.6 mmol) was added and themixture was stirred at 25° C. for 18 hr. The rxn contents were pouredinto ice/water (v/v=1/1) (150 mL) and stirred for 20 min. The aq phasewas extracted with EA (40 mL×3). The combined organic phase was washedwith brine (20 mL×2), dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified byprep-HPLC to afford the title compound (57.35 mg, 22%) as a white solid.¹H NMR (DMSO-d₆, 400 MHz): δ 8.63 (s, 1H), 8.26 (s, 1H), 8.04 (dd,J₁=8.8 Hz, J₂=2.4 Hz 1H), 7.95 (d, J=2.4 Hz, 1H), 7.56 (d, J=8.8 Hz,1H), 7.31 (s, 1H), 4.90-4.84 (brs, 1H), 3.44 (s, 3H), 3.32 (q, J=7.2 Hz,2H), 1.85-1.83 (m, 4H), 1.69-1.61 (m, 4H), 1.15 (t, J=7.2 Hz, 3H). LCMS:452.2 (M+H)⁺.

Example 374:5-(2-cyclopentyloxy-5-ethylsulfonylphenyl)-7-methylimidazo[1,5-a]pyrazin-8-one

The title compound was prepared in a manner similar to Example 373, bysubstituting cyclopentanol for 4,4-difluorocyclohexan-1-ol in Step 3. ¹HNMR (DMSO-d₆, 400 MHz): δ 8.34 (s, 1H), 8.16 (s, 1H), 8.02 (d, J=8.8 Hz,1H), 7.91 (s, 1H), 7.42 (d, J=8.8 Hz, 1H), 7.24 (s, 1H), 5.04-5.01 (brs,1H), 3.43 (s, 3H), 3.31 (q, J=6.8 Hz, 2H), 1.91-1.80 (m, 2H), 1.62-1.30(m, 6H), 1.14 (t, J=6.8 Hz, 3H). LCMS: 402.2 (M+H)⁺.

Example 375:5-[2-(cyclopropylmethylamino)-5-ethylsulfonylphenyl]-7-methylimidazo[1,5-a]pyrazin-8-one

The title compound was prepared in a manner similar to Example 373, bysubstituting cyclopropylmethanamine for 4,4-difluorocyclohexan-1-ol inStep 3. ¹H NMR (DMSO-d₆, 400 MHz): δ 8.28-8.24 (m, 2H), 7.76 (d, J=8.8Hz, 1H), 7.64 (s, 1H), 6.98 (d, J=8.8 Hz, 1H), 6.47-6.41 (brs, 1H), 3.44(s, 3H), 3.18 (q, J=7.2 Hz, 2H), 3.06-3.01 (m, 2H), 1.12 (t, J=6.8 Hz,3H), 1.06-0.98 (m, 1H), 0.42-0.37 (m, 2H), 0.16-0.11 (m, 2H). LCMS:387.2 (M+H)⁺.

Example 376:5-[2-(2,4-difluorophenoxy)-5-ethylsulfonylphenyl]-7-methylimidazo[1,5-a]pyrazin-8-one

The title compound was prepared in a manner similar to Example 373, bysubstituting 2,4-difluorophenol for 4,4-difluorocyclohexan-1-ol in Step3. ¹H NMR (CDCl₃, 400 MHz): δ 8.05 (d, J=2.4 Hz, 1H), 8.03 (s, 1H), 7.97(dd, J₁=8.8 Hz, J₂=2.4 Hz 1H), 7.16-7.10 (m, 1H), 7.05-7.00 (m, 1H),6.98-6.93 (m, 1H), 7.97 (dd, J₁=8.8 Hz, J₂=1.2 Hz 1H), 3.55 (s, 3H),3.18 (q, J=7.2 Hz, 2H), 1.36 (t, J=7.2 Hz, 3H). LCMS: 446.1 (M+H)⁺.

Example 377:7-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-5-methylfuro[3,2-c]pyridine-4-oneStep 1: 7-bromo-5-methylfuro[3,2-c]pyridin-4-one

To a suspension of 7-bromo-5H-furo[3,2-c]pyridin-4-one (250 mg, 1.17mmol) in DMF (5 mL) cooled to 0° C. was added HNa (56 mg, 1.4 mmol, 60%dispersion in mineral oil) in three portions. After stirring at roomtemp for 45 min, MeI (87 μL, 1.4 mmol) was added drop wise over 5 min.The rxn was allowed to warm up to room temp stirred for 2 hr. It wasthen cooled to 0° C. followed by addition of sat. aq NH₄Cl (5 mL) dropwise. The resulting mixture was extracted with EtOAc (3×5 mL). Thecombined organic layers were dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified by silicagel CC to afford the title compound. LCMS: 227.9 (M+H)⁺.

Step 2:5-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)furo[3,2-c]pyridin-4-one

The title compound was prepared in a manner similar to Example 255, step4, by substituting 7-bromo-5-methylfuro[3,2-c]pyridin-4-one forN-[4-(cyclopropylmethoxy)-3-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethane-1-sulfonamide.LCMS: 276.1 (M+H)⁺.

Step 3:7-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-5-methylfuro[3,2-c]pyridin-4-one

The title compound was prepared in a manner similar to Example 197, bysubstituting5-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)furo[3,2-c]pyridin-4-onefor2-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane,and 2-bromo-1-(cyclopropylmethoxy)-4-methylsulfonylbenzene for4-bromo-2-methyl-6-(trifluoro-methyl)isoquinolin-1-one. ¹H NMR (CDCl₃,400 MHz): δ 8.05 (s, 1H), 7.92 (dd, J₁=8.6 Hz, J₂=1.8 Hz, 1H), 7.50 (m,2H), 7.07 (m, 2H), 3.95 (d, J=6.7 Hz, 2H), 3.70 (s, 3H), 3.1 (s, 3H),1.15 (m, 1H), 0.57 (m, 2H), 0.28 (m, 2H). LCMS: 374.1 (M+H)⁺.

Example 378:7-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-5-methylfuro[3,2-c]pyridine-4-one

The title compound was prepared in a manner similar to Example 197, bysubstituting2-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolanefor2-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane,and 7-bromo-5-methylfuro[3,2-c]pyridin-4-one for4-bromo-2-methyl-6-(trifluoromethyl)isoquinolin-1-one. ¹H NMR (DMSO-d₆,400 MHz): δ 7.88 (m, 4H), 7.33 (d, J=9.4 Hz, 1H), 7.01 (d, J=2.0 Hz,1H), 4.02 (d, J=6.8 Hz, 2H), 3.58 (s, 3H), 3.28 (m, 2H), 1.12 (t, J=7.4Hz, 3H), 1.08 (m, 1H), 0.45 (m, 2H), 0.24 (m, 2H). LCMS: 388.1 (M+H)⁺.

Example 379:N-[4-(2,4-difluorophenoxy)-3-(5-methyl-4-oxofuro[3,2-c]pyridin-7-yl)phenyl]ethanesulfonamide

The title compound was prepared in a manner similar to Example 197, bysubstitutingN-[4-(2,4-difluorophenoxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethane-sulfonamidefor2-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane,and 7-bromo-5-methylfuro[3,2-c]pyridin-4-one for4-bromo-2-methyl-6-(trifluoro-methyl)isoquinolin-1-one. ¹H NMR (DMSO-d₆,400 MHz): δ 9.83 (s, 1H), 7.85 (d, J=2.0 Hz, 1H), 7.78 (s, 1H), 7.37 (m,2H), 7.24 (dd, J₁=8.8 Hz, J₂=2.7 Hz, 1H), 7.14 (m, 1H), 7.03 (m, 1H),6.97 (d, J=2.1 Hz, 1H), 6.93 (d, J=8.8 Hz, 1H), 3.54 (s, 3H), 3.12 (q,J=7.3 Hz, 2H), 1.12 (t, J=7.3 Hz, 3H). LCMS: 461.2 (M+H)⁺.

Example 380:N-[4-(2,4-difluorophenoxy)-3-(5-methyl-4-oxofuro[3,2-c]pyridin-7-yl)phenyl]methanesulfonamide

The title compound was prepared in a manner similar to Example 197, bysubstitutingN-[4-(2,4-difluorophenoxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanesulfonamidefor2-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolaneand 7-bromo-5-methylfuro[3,2-c]pyridin-4-one for4-bromo-2-methyl-6-(trifluoro-methyl)isoquinolin-1-one. ¹H NMR (DMSO-d₆,400 MHz): δ 9.77 (s, 1H), 7.85 (d, J=2.1 Hz, 1H), 7.79 (s, 1H), 7.38 (m,2H), 7.25 (dd, J₁=8.8 Hz, J₂=2.8 Hz, 1H), 7.12 (m, 1H), 7.04 (m, 1H),6.97 (d, J=2.1 Hz, 1H), 6.94 (d, J=8.8 Hz, 1H), 3.54 (s, 3H), 3.02 (s,3H). LCMS: 447.1 (M+H)⁺.

Example 381:4-(cyclopropylmethoxy)-5-(1-methyl-6-oxopyridin-3-yl)-1-(methylsulfonylmethyl)pyridin-2-oneStep 1: 5-bromo-4-(cyclopropylmethoxy)-2-methoxypyridine

To a soln of cyclopropylmethanol (446 mg, 6.18 mmol) in THF (10 mL) wasadded NaH (247 mg, 6.18 mmol, 60% in mineral oil) in one portion at 0°C. The rxn mixture was warmed up to 20° C. over a period of 30 min andstirred at 20° C. for 10 min. Then 5-bromo-4-chloro-2-methoxypyridine(550 mg, 2.47 mmol) was added in one portion and the mixture was stirredat 70° C. for 4 hr. The mixture was diluted with satd ammonium aq soln(50 mL) and extracted by EtOAc (2×30 mL). The combined organic layerswere dried over anhydrous Na₂SO₄, filtered, and concentrated to give thecrude product which was purified by CC (PE:EA=20:1 to 10:1) to affordthe title compound (450 mg, 70.6%) as colorless oil. ¹H NMR (CDCl₃, 400MHz): δ 8.11 (s, 1H), 6.18 (s, 1H), 3.90 (s, 3H), 3.89-3.88 (m, 2H),1.39-1.27 (m, 1H), 0.70-0.67 (m, 2H), 0.46-0.43 (m, 2H). LCMS (M+H)⁺:258.0; (M+1)⁺: 260.0.

Step 2: 5-bromo-4-(cyclopropylmethoxy)pyridin-2-ol

To a soln of the title compound from step 1 (450 mg, 1.74 mmol) in DMF(5 mL) was added LiCl (370 mg, 8.72 mmol) and TsOH.H₂O (1.52 g, 8.72mmol) at room temp. The mixture was heated to 120° C. and stirred for 1hr, then diluted with H₂O (100 mL) and extracted with EtOAc (3×100 mL).The combined organic phase was washed with satd brine (2×200 mL), driedover anhydrous Na₂SO₄, filtered and concentrated under reduced pressureto afford the title compound (380 mg, yield: 88.9%) as yellow solidwhich used directly for the next step without further purification. ¹HNMR (CDCl₃, 400 MHz) δ 7.49 (s, 1H), 5.91 (s, 1H), 3.87 (d, J=6.8 Hz,2H), 1.36-1.22 (m, 1H), 0.71-0.67 (m, 2H), 0.46-0.42 (m, 2H). LCMS:244.0 (M+1)⁺; 246.0 (M+1)⁺.

Step 3:5-bromo-4-(cyclopropylmethoxy)-1-(methylsulfanylmethyl)pyridin-2-one

To a soln of the title compound from Step 2 (330 mg, 1.35 mmol) in DMF(5 mL) was added NaH (40 mg, 2 mmol, 60% in mineral oil) at 0° C. Themixture was stirred at 0° C. for 30 min. Then, chloromethyl methylsulfide (131 mg, 1.35 mmol) was added. The mixture was warmed to roomtemp and stirred for 5 hr. The mixture was quenched with sat. aq NH₄Cl(30 mL) and extracted with EA (10 mL×3). The combined organic layerswere washed with satd brine (20 mL×2), dried over anhydrous Na₂SO₄,filtered and concentrated under vacuum. The residue was purified by CC(PE:EA=3:1) to afford the title compound (205 mg, 50%) as yellow oil. ¹HNMR (CDCl₃, 400 MHz): δ 7.60 (s, 1H), 5.86 (s, 1H), 4.96 (s, 1H), 3.84(d, J=6.8 Hz, 2H), 2.17 (s, 3H), 1.32-1.25 (m, 1H), 0.70-0.67 (m, 2H),0.41-0.39 (m, 2H).

Step 4:5-bromo-4-(cyclopropylmethoxy)-1-(methylsulfonylmethyl)pyridin-2-one

To a soln of the title compound from Step 3 (150 mg, 0.5 mmoL) in DCM (5mL), was added mCPBA (340 mg, 1.9 mmol). The mixture was stirred at 15°C. for 2.5 hr. H₂O (30 mL) was added and the resulting mixture wasextracted with EtOAc (120 mL×3). The combined organic phases were washedwith satd brine (40 mL×2), dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified by CC onsilica gel (PE:EA=5:1 to 2:1) to afford the title compound (120 mg, 72%)as a yellow solid. ¹H NMR (CDCl₃, 400 MHz): δ 7.60 (s, 1H), 5.91 (s,1H), 5.10 (s, 2H), 3.89 (d, J=6.8 Hz, 2H), 2.98 (s, 3H), 0.90-0.86 (m,1H), 0.75-0.70 (m, 2H), 0.45-0.42 (m, 2H). LCMS: 335.9 (M+1)⁺; 337(M+1)⁺.

Step 5:4-(cyclopropylmethoxy)-5-(1-methyl-6-oxopyridin-3-yl)-1-(methylsulfonylmethyl)pyridin-2-one

The title compound from step 4 (50 mg, 0.15 mmol),1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one(42 mg, 0.18 mmol), Pd(dppf)Cl₂ (11 mg, 14.9 umol) and K₃PO₄ (63 mg, 0.3mmol) in dioxane (5 mL) and H₂O (5 drops) were degassed and then heatedto 70° C. under N₂ overnight. The rxn mixture was then concentratedunder reduced pressure. The residue was purified by CC (PE:DCM:EA=3:0:1to 0:1:4) followed by preparative HPLC to afford the title compound(17.09 mg, 31.5%) as an off-white solid. ¹H NMR (CDCl₃, 400 MHz): δ 7.50(dd, J₁=9.2 Hz, J₂=2.4 Hz, 1H), 7.43 (d, J=2.4 Hz, 1H), 6.71 (d, J=9.2Hz, 1H), 5.96 (s, 1H), 5.16 (s, 2H), 3.86 (d, J=6.8 Hz, 1H), 3.63 (s,3H), 2.99 (s, 3H), 1.26-1.21 (m, 1H), 0.70-0.66 (m, 2H), 0.36-0.32 (m,2H). LCMS: 365.0 (M+1)⁺.

Example 382:5-[4-(cyclopropylmethoxy)-1-(methylsulfonylmethyl)-6-oxopyridin-3-yl]-1,3-dimethylpyridin-2-one

The title compound was prepared in a manner similar to Example 381, bysubstituting1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-onefor1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one instep 5. ¹H NMR (CDCl₃, 400 MHz): δ 7.35 (s, 1H), 7.32 (s, 2H), 5.97 (s,1H), 5.16 (s, 2H), 3.87 (s, J=7.2 Hz, 2H), 3.62 (s, 3H), 2.99 (s, 3H),2.20 (s, 3H), 1.25-0.24 (m, 1H), 0.70-0.65 (m, 2H), 0.36-0.35 (m, 2H).LCMS: 379.0 (M+1)⁺.

Example 383:4-[4-(cyclopropylmethoxy)-1-(methylsulfonylmethyl)-6-oxopyridin-3-yl]-7-fluoro-2-methylisoquinolin-1-one

The title compound was prepared in a manner similar to Example 381, bysubstituting7-fluoro-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1-onefor1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one instep 5. ¹H NMR (CDCl₃, 400 MHz): δ 8.13 (dd, J₁=9.2 Hz, J₂=2.4 Hz, 1H),7.37 (s, 1H), 7.35-7.32 (m, 1H), 7.30-7.28 (m, 1H), 7.03 (s, 1H), 5.99(s, 3H), 5.13 (d, J=13.6 Hz, 1H), 4.91 (d, J=13.6 Hz, 1H), 3.78 (t,J=6.4 Hz, 2H), 3.65 (s, 3H), 3.04 (s, 3H), 1.03-0.97 (m, 1H), 0.48-0.42(m, 2H), 0.11 (s, 2H). LCMS: 433.1 (M+1)⁺.

Example 384:4-[4-(cyclopropylmethoxy)-1-(methylsulfonylmethyl)-6-oxopyridin-3-yl]-2-methylisoquinolin-1-one

The title compound was prepared in a manner similar to Example 381, bysubstituting2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1-onefor1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one instep 5. ¹H NMR (CDCl₃, 400 MHz): δ 8.49 (d, J=8.0 Hz, 1H), 7.61 (t,J=7.2 Hz, 1H), 7.52 (t, J=7.2 Hz, 1H), 7.38 (s, 1H), 7.27 (d, J=8.0 Hz,1H), 7.07 (s, 1H), 5.99 (s, 1H), 5.45 (d, J=14.4 Hz, 1H), 4.89 (d,J=14.4 Hz, 1H), 3.79 (t, J=8.0 Hz, 2H), 3.65 (s, 3H), 3.04 (s, 3H),1.02-0.96 (m, 1H), 0.46-0.39 (m, 2H), 0.10 (s, 2H). LCMS: 415.1 (M+1)⁺.

Example 385:5-[4-(2,4-difluorophenoxy)-1-(methylsulfonylmethyl)-6-oxopyridin-3-yl]-1,3-dimethylpyridin-2-oneStep 1:5-bromo-4-(2,4-difluorophenoxy)-1-(methylsulfonylmethyl)pyridin-2-one

The title compound was prepared in a manner similar to Example 381 Steps1 through 4, by substituting 2,4-difluorophenol for cyclopropylmethanolin step 1. ¹H NMR (CDCl₃, 400 MHz) δ 7.71 (s, 1H), 7.21 (m, 1H), 7.01(m, 2H), 5.66 (s, 1H), 5.1 (s, 2H), 2.96 (s, 3H).

Step 2:5-[4-(2,4-difluorophenoxy)-1-(methylsulfonylmethyl)-6-oxopyridin-3-yl]-1,3-dimethylpyridin-2-one

The title compound was prepared in a manner similar to Example 382, bysubstituting the title compound from Step 1 for5-bromo-4-(cyclopropylmethoxy)-1-(methylsulfonylmethyl)pyridin-2-one. ¹HNMR (CDCl₃, 400 MHz) δ 7.40 (s, 1H), 7.37 (s, 1H), 7.33 (s, 1H),7.21-7.11 (m, 1H), 7.07-6.93 (m, 2H), 5.68 (s, 1H), 5.16 (s, 2H), 3.61(s, 3H), 2.99 (s, 3H), 2.20 (s, 3H). LCMS: 437.0 (M+1)⁺.

Example 386:4-(2,4-difluorophenoxy)-5-(1-methyl-6-oxopyridin-3-yl)-1-(methylsulfonylmethyl)pyridin-2-one

The title compound was prepared in a manner similar to Example 381, bysubstituting5-bromo-4-(2,4-difluorophenoxy)-1-(methylsulfonylmethyl)pyridin-2-onefor5-bromo-4-(cyclo-propylmethoxy)-1-(methylsulfonylmethyl)pyridin-2-one instep 5. ¹H NMR (CDCl₃, 400 MHz): δ 7.53 (dd, J₁=2.4 Hz, J₂=9.6 Hz, 1H),7.46 (d, J=2.4 Hz, 1H), 7.44 (s, 1H), 7.19-7.13 (m, 1H), 7.07-7.00 (m,1H), 7.00-6.93 (m, 1H), 6.64 (d, J=9.2 Hz, 1H), 5.68 (s, 1H), 5.17 (s,2H), 3.61 (s, 3H), 2.98 (s, 3H). LCMS: 423.0 (M+1)⁺.

Example 387:4-[4-(2,4-difluorophenoxy)-1-(methylsulfonylmethyl)-6-oxopyridin-3-yl]-2-methylisoquinolin-1-one

The title compound was prepared in a manner similar to Example 384, bysubstituting5-bromo-4-(2,4-difluorophenoxy)-1-(methylsulfonylmethyl)pyridin-2-onefor5-bromo-4-(cyclo-propylmethoxy)-1-(methylsulfonylmethyl)pyridin-2-one.¹H NMR (CDCl₃, 400 MHz): δ 8.50 (d, J=8.0 Hz, 1H), 7.72-7.67 (m, 1H),7.57-7.52 (m, 1H), 7.49 (d, J=9.2 Hz, 2H), 7.20 (s, 1H), 7.08-7.02 (m,1H), 7.01-6.94 (m, 1H), 6.93-6.86 (m, 1H), 5.74 (s, 1H), 5.46 (d, J=14.4Hz, 1H), 4.92 (d, J=14.4 Hz, 1H), 3.68 (s, 3H), 3.05 (s, 3H). LCMS:473.0 (M+1)⁺.

Example 388:5-(2-but-2-ynoxy-5-methylsulfonylphenyl)-1,3-dimethylpyridin-2-one Step1: 5-(2-fluoro-5-methylsulfonylphenyl)-1,3-dimethylpyridin-2-one

A mixture of1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one(2.50 g, 10.0 mmol), 2-bromo-1-fluoro-4-methylsulfonylbenzene (2.54 g,10.0 mmol), CsF (3.8 g, 25.0 mmol), Pd(dppf)Cl₂ (0.73 g, 1.0 mmol) inDME (50 mL), and MeOH (25 ml) was stirred at 80° C. for 18 hr under N₂.The mixture was concentrated and the residue was purified by CC(PE:EA=2:1 to 0:1) to give the title compound (1.8 g, 61%) as a redsolid. LCMS: 295.9 (M+H)⁺.

Step 2:5-(2-but-2-ynoxy-5-methylsulfonylphenyl)-1,3-dimethylpyridin-2-one

To a soln of but-2-yn-1-ol (191 mg, 2.72 mmol) in anhydrous DMF (3 mL)was added NaH (109 mg, 2.72 mmol, 60% in mineral oil) at 0° C. Themixture was stirred at this temp for 1 hr. The title compound from Step1 (200 mg, 0.68 mmol) was added and the rxn mixture was stirred at 0° C.for 2 hr. After this time, it was quenched with sat. NH₄Cl soln (20 mL)and extracted with EtOAc (20 mL×3). The combined organic layers werewashed with brine (40 mL), dried over Na₂SO₄, filtered and concentratedto give a crude product that was purified by prep-HPLC to give the titlecompound (56.01 mg, 23.9%) as a light yellow solid. ¹H NMR (CDCl₃, 400MHz): δ 7.88 (dd, J₁=8.8 Hz, J₂=2.0 Hz, 1H), 7.81 (d, J=2.0 Hz, 1H),7.46 (s, 2H), 7.24 (d, J=8.8 Hz, 1H), 4.79 (d, J=2.0 Hz, 2H), 3.62 (s,3H), 3.08 (s, 3H), 2.22 (s, 3H), 1.87 (s, 3H). LCMS: 346.0 (M+H)⁺.

Example 389:5-(2-but-2-ynoxy-5-ethylsulfonylphenyl)-3-methoxy-1-methylpyridin-2-oneStep 1:5-(5-ethylsulfonyl-2-fluorophenyl)-3-methoxy-1-methylpyridin-2-one

To a soln of 5-bromo-3-methoxy-1-methylpyridin-2-one (694 mg, 3.18mmol),2-(5-ethylsulfonyl-2-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(1 g, 3.18 mmol), Pd(dppf)Cl₂ (233 mg, 318.00 μmol) in C₄H₈O₂ (26 mL)and H₂O (2.6 mL) was added K₃PO₄ (2.02 g, 9.54 mmol, 3.00 Eq). The rxnwas stirred at 70° C. under N₂ for 6 hr; then concentrated and theresidue purified by CC (PE:EA=3:1 to 1:2) to afford the title compound(0.9 g, 87%) as a brown solid. ¹H NMR (CDCl₃, 400 MHz): δ 7.93 (dd,J₁=7.2 Hz, J₂=2.0 Hz, 1H), 7.88-7.84 (m, 1H), 7.35 (dd, J₁=10.0 Hz,J₂=8.8 Hz, 1H), 7.23 (d, J=1.6 Hz, 1H), 6.83 (s, 1H), 3.89 (s, 3H), 3.67(s, 3H), 3.16 (q, J=7.6 Hz, 2H), 1.33 (t, J=7.6 Hz, 3H). LCMS: 325.9(M+H)⁺.

Step 2:5-(2-but-2-ynoxy-5-ethylsulfonylphenyl)-3-methoxy-1-methylpyridin-2-one

The title compound was prepared in a manner similar to Example 388, Step2, by substituting5-(5-ethylsulfonyl-2-fluorophenyl)-3-methoxy-1-methylpyridin-2-one for5-(2-fluoro-5-methylsulfonylphenyl)-1,3-dimethylpyridin-2-one. ¹H NMR(CDCl₃, 400 MHz): δ 7.88 (d, J=8.8 Hz, 1H), 7.80 (s, 1H), 7.23 (d, J=8.4Hz, 1H), 7.19 (s, 1H), 6.97 (s, 1H), 4.78 (s, 2H), 3.83 (s, 3H), 3.70(s, 3H), 3.15 (q, J=7.2 Hz, 2H), 1.87 (s, 3H), 1.32 (t, J=7.2 Hz, 3H).LCMS: 376.0 (M+H)⁺.

Example 390:5-(5-ethylsulfonyl-2-pent-2-ynoxyphenyl)-3-methoxy-1-methylpyridin-2-one

The title compound was prepared in a manner similar to Example 389, bysubstituting pent-2-yn-1-ol for but-2-yn-1-ol in Step 2. ¹H NMR (CDCl₃,400 MHz) δ 7.86 (dd, J₁=8.8 Hz, J₂=2.0 Hz, 1H), 7.79 (d, J=2.4 Hz, 1H),7.23 (d, J=8.8 Hz, 1H), 7.18 (d, J=2.0 Hz, 1H), 6.94 (d, J=1.6 Hz, 1H),4.80 (s, 2H), 3.87 (s, 3H), 3.67 (s, 3H), 3.15 (q, J=7.6 Hz, 2H), 2.24(q, J=7.6 Hz, 2H), 1.32 (t, J=7.6 Hz, 3H), 1.14 (t, J=7.6 Hz, 3H). LCMS:390.2 (M+H)⁺.

Example 391:5-[2-(3-cyclopropylprop-2-ynoxy)-5-ethylsulfonylphenyl]-3-methoxy-1-methylpyridin-2-one

The title compound was prepared in a manner similar to Example 389, bysubstituting 3-cyclopropylprop-2-yn-1-ol for but-2-yn-1-ol in Step 2. ¹HNMR (CDCl₃, 400 MHz) δ 7.87 (d, J=8.8 Hz, 1H), 7.79 (s, 1H), 7.22-7.20(m, 2H), 7.00 (s, 1H), 4.77 (s, 2H), 3.88 (s, 3H), 3.70 (s, 3H), 3.15(q, J=7.2 Hz, 2H), 1.32 (t, J=7.2 Hz, 3H), 1.31-1.29 (m, 1H), 0.84-0.81(m, 2H), 0.69-0.67 (m, 2H). LCMS: 402.0 (M+H)⁺.

Example 392:N-[4-(2,4-difluorophenoxy)-3-[1-methyl-6-oxo-5-(trifluoromethyl)pyridin-3-yl]phenyl]ethanesulfonamideStep 1: 5-bromo-1-methyl-3-(trifluoromethyl)pyridin-2-one

To a soln of 5-bromo-3-(trifluoromethyl)pyridin-2-ol (6 g, 25 mmol)stirred at room temp in THF (5 mL) was added NaH (1.5 g, 37 mmol, 60% inmineral oil). After stirring for 30 min, methyl iodide (7.1 g, 50 mmol)was added. After stirring at room temp for 3 hr, the rxn mixture wastreated with H₂O (100 mL) and extracted with EtOAc (100 mL×3). Thecombined organic layers were washed with brine (100 mL), dried overNa₂SO₄, filtered, and concentrated in vacuo to afford the title compound(6 g, 97%) as a tan solid. The solid was carried forward without anyfurther purification. ¹H NMR (CDCl3, 400 MHz): δ 7.79 (d, J=2.0 Hz, 1H),7.65 (d, J=2.0 Hz, 1H), 3.60 (s, 3H). LCMS (M+H)⁺: 256.

Step 2:1-methyl-5-(3,3,4,4-tetramethylborolan-1-yl)-3-(trifluoromethyl)pyridin-2-one

A suspension of compound5-bromo-1-methyl-3-(trifluoromethyl)pyridin-2-one (3 g, 11.8 mmol),4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(3.6 g, 14.1 mmol), KOAc (3 g, 30.6 mmol), and Pd(dppf)₂Cl₂ (200 mg) indioxane (50 mL) was stirred at 90° C. for 4 hr. After the rxn mixturewas concentrated in vacuo, the resulting residue was purified by CC(PE:EA=3:1 to 1:1) to give the title compound (1.2 g, 34%) as a redsolid. ¹H NMR (CDCl₃, 400 MHz): δ 8.02 (d, J=2.0 Hz, 1H), 7.94 (d, J=2.0Hz, 1H), 3.60 (s, 3H), 1.32 (s, 12H). LCMS (M+H)⁺: 304.

Step 3:5-[2-(2,4-difluorophenoxy)-5-ethylsulfonylphenyl]-1-methyl-3-(trifluoromethyl)pyridin-2-one

A mixture of1-methyl-5-(3,3,4,4-tetramethylborolan-1-yl)-3-(trifluoromethyl)pyridin-2-one(100 mg, 0.33 mmol),1-(2-bromo-4-ethylsulfonylphenoxy)-2,4-difluorobenzene (100 mg, 0.27mmol), Pd(dppf)Cl₂ (24 mg) and K₃PO₄ (107 mg, 0.80 mmol) in dioxane (4mL) and H₂O (1 mL) was purged with N₂, capped, and heated to 90° C. for4 hr. After the mixture was filtered through a short bed of celite, thefiltrate was concentrated in vacuo and purified by prep-HPLC afford thetitle compound (43 mg, 34%) as a white solid. ¹H NMR (CDCl₃, 400 MHz): δppm 8.11 (s, 1H) 7.88 (s, 2H) 7.80 (m, 1H), 7.23-7.10 (m, 1H) 7.09-6.91(m, 2H) 6.91-6.78 (m, 1H) 6.25 (s, 1H) 3.70 (s, 3H) 3.15 (q, J=7.2 Hz,2H) 1.31 (t, J=7.2 Hz, 3H). LCMS (M+H)⁺: 474.

Example 393:4-[2-(cyclopropylmethoxy)-5-propan-2-ylsulfonylphenyl]-6-methoxy-2-methylisoquinolin-1-one

Bromo-6-methoxy-2-methylisoquinolin-1-one (prepared as reportedpreviously in WO 2013/142390) was reacted with4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolanein a manner similar to Example 248, step 2, to give6-methoxy-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1-onewhich was then reacted with the title compound of Example 364, step 1,in a manner similar to Example 364, step 2, to give the title compound.¹H NMR (CDCl₃, 400 MHz): δ 8.45 (d, J=8.4 Hz, 1H), 7.91 (dd, J₁=2.0 Hz,J₂=8.8, 1H), 7.06-7.27 (m, 3H), 6.53 (d, J=2.8 Hz, 1H), 3.89 (m, 2H),3.78 (s, 3H), 3.65 (s, 3H), 3.22 (m, 1H), 1.33 (d, J=6.4 Hz, 6H), 1.03(q, J=6.8 Hz, 1H), 0.45 (m, 2H), 0.14 (s, 2H). LCMS: 442.0 (M+H)⁺.

Example 394:5-[2-(cyclopropylmethoxy)-5-propan-2-ylsulfonylphenyl]-1,3-dimethylpyridin-2-one

The title compound of Example 364, step 1 was reacted with1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-onein a manner similar to Example 364, step 2 to give the title compound.¹H NMR (CDCl3, 400 MHz): δ 7.75-7.79 (m, 2H), 7.59 (s, 1H), 7.03 (d,J=8.4 Hz, 1H), 3.96 (d, J=6.8 Hz, 2H), 3.67 (s, 3H), 3.15-3.25 (m, 1H),2.24 (s, 3H), 1.31 (d, J=7.2 Hz, 6H), 1.27 (d, J=7.2 Hz, 1H), 0.66-0.70(m, 2H), 0.38 (q, J=5.2 Hz, 2H). LCMS: 376.0 (M+H)⁺.

Example 395:N-[3-(1,5-dimethyl-6-oxopyridin-3-yl)-5-phenylmethoxyphenyl]ethanesulfonamideStep 1: N-(3-bromo-5-phenylmethoxyphenyl)ethanesulfonamide

Ethylsulfonyl chloride (113 μL, 1.2 mmol) was added dropwise to astirred soln of 3-bromo-5-phenylmethoxyaniline (284 mg, 1.0 mmol) andpyridine (247 μL, 3.1 mmol) in DCM (5 mL) at 0° C. under N₂. After themixture was warmed to room temp and stirred for 14 hr, it was treatedwith 1N HCl (1 mL) and extracted with DCM (3×5 mL); the combined organicextracts were washed with satd bicarbonate soln (aq), dried over Na₂SO₄,filtered and concentrated in vacuo. The crude solid was purified by CCusing EtOAc (5% to 95%) in hexanes to afford the title compound (345 mg,94%) as an amber oil that solidified upon standing. LCMS (M+H)⁺: 371.

Step 2:N-[3-(1,5-dimethyl-6-oxopyridin-3-yl)-5-phenylmethoxyphenyl]ethanesulfonamide

A mixture of N-(3-bromo-5-phenylmethoxyphenyl)ethanesulfonamide (60 mg,0.16 mmol),1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one(40 mg, 0.16 mmol), Pd(dppf)Cl₂ (12 mg) and K₃PO₄ (88 mg, 0.40 mmol) indioxane (1.5 mL) and H₂O (150 μL) was purged with N₂, capped, and heatedto 75° C. for 2 hr. After the mixture was filtered through a short bedof celite, the filtrate was concentrated in vacuo and purified by silicagel CC using MeOH (0% to 10%) in DCM to afford the title compound (69mg, 94%) as an off-white solid. ¹H NMR (400 MHz, DMSO-d₆): δ ppm1.15-1.24 (m, 3H) 2.04-2.13 (m, 3H) 3.04-3.17 (m, 2H) 3.48-3.54 (m, 3H)5.08-5.17 (m, 2H) 6.74-6.80 (m, 1H) 6.90-6.98 (m, 2H) 7.33-7.49 (m, 5H)7.59-7.63 (m, 1H) 7.90-7.95 (m, 1H) 9.57-10.01 (bs, 1H). LCMS (M+H)⁺:413.

Examples 396-482 in Table 21 were prepared using Suzuki conditions toappend an appropriately substituted aryl group to an appropriatelysubstituted pyridinone. Chemical manipulation subsequent to the Suzukireaction was also carried out as needed to give the title compound.

TABLE 21 Chemical Synthesis MS Example Structure Name (M + H) 396

5-[2-(2,4-difluoroanilino)-5- ethylsulfonylphenyl]-1,3-dimethylpyridin-2-one 419.1 397

5-[2-[(4,4-difluorocyclohexyl)amino]- 5-ethylsulfonylphenyl]-1,3-dimethylpyridin-2-one 425.1 398

5-[2-(2,4-difluoroanilino)-5- methylsulfonylphenyl]-1,3-dimethylpyridin-2-one 405.1 399

5-[2-(cyclopropylmethoxy)-5- ethylsulfonylphenyl]-3-methoxy-1-methylpyridin-2-one 378.1 400

5-[2-(2,4-difluorophenoxy)-5- (methylsulfonylmethyl)phenyl]-3-methoxy-1-methylpyridin-2-one 436.0 401

5-[2-(4-trans-hydroxycyclohexyl)oxy- 5-methylsulfonylphenyl]-1,3-dimethylpyridin-2-one 392.1 402

N-[4-(2,4-difluorophenoxy)-3-(1- methyl-5-methylsulfanyl-6-oxopyridin-3-yl)phenyl] ethanesulfonamide 467.10 403

5-[2-(4-cis-aminocyclohexyl)oxy-5- methylsulfonylphenyl]-1,3-dimethylpyridin-2-one 391.2 404

5-[2-(4-trans-aminocyclohexyl)oxy-5- methylsulfonylphenyl]-1,3-dimethylpyridin-2-one 391.1 405

1,3-dimethyl-5-[5-methylsulfonyl-2- (3,3,3-trifluoropropoxy)phenyl]pyridin-2-one 390.0 406

5-[2-(2,4-difluorophenoxy)-5- (methylsulfonylmethyl)phenyl]-1-(2-hydroxyethyl)-3-methylpyridin-2-one 450.2 407

5-[5-(ethylsulfonylmethyl)-2-(2,2,2- trifluoroethoxy)phenyl]-1-(2-hydroxyethyl)-3-methylpyridin-2-one 434.1 408

5-[2-(cyclopropylmethylamino)-5- ethylsulfonylphenyl]-1-methyl-3-(methylamino)pyridin-2-one 376.2 409

5-[2-(cyclopropylmethoxy)-5- ethylsulfonylphenyl]-1-methyl-3-(methylamino)pyridin-2-one 377.2 410

N-[4-(2,4-difluorophenoxy)-3-[1- methyl-5-(methylamino)-6-oxopyridin-3-yl]phenyl] ethanesulfonamide 450.1 411

5-[5-(ethylsulfonylmethyl)-2-(2,2,2- trifluoroethoxy)phenyl]-1,3-dimethylpyridin-2-one 404.1 412

N-[4-(2,4-difluorophenoxy)-3-[1- methyl-5-(methylamino)-6-oxopyridin-3-yl]phenyl] methanesulfonamide 436.0 413

5-[2-[(4,4-difluorocyclohexyl)amino]- 5-methylsulfonylphenyl]-1,3-dimethylpyridin-2-one 411.0 414

5-[2-(cyclopropylmethylamino)-5- ethylsulfonylphenyl]-3-methoxy-1-methylpyridin-2-one 377.1 415

5-[2-(4,4-difluorocyclohexyl)oxy-5- methylsulfonylphenyl]-1,3-dimethylpyridin-2-one 412.1 416

5-[2-(cyclopentylamino)-5- ethylsulfonylphenyl]-1,3-dimethylpyridin-2-one 375.2 417

5-[2-(cyclopentylamino)-5- methylsulfonylphenyl]-1,3-dimethylpyridin-2-one 361.1 418

3-chloro-1-methyl-5-[5- (methylsulfonylmethyl)-2-(2,2,2-trifluoroethoxy)phenyl]pyridin-2-one 410.0 419

5-(2-cyclopentyloxy-5- methylsulfonylphenyl)-1,3- dimethylpyridin-2-one362.1 420

1,3-dimethyl-5-[5-methylsulfonyl-2- (oxan-4-yloxy)phenyl]pyridin-2-one378.1 421

3-fluoro-1-methyl-5-[5- (methylsulfonylmethyl)-2-(2,2,2-trifluoroethoxy)phenyl]pyridin-2-one 394.1 422

5-[2-(cyclopropylmethylamino)-5- methylsulfonylphenyl]-1,4-dimethylpyridin-2-one 347.0 423

5-[2-(cyclopropylmethylamino)-5- ethylsulfonylphenyl]-1,4-dimethylpyridin-2-one 361.1 424

N-[4-(1-methyl-6-oxopyridin-3-yl)-5- phenylthiophen-2-yl]ethanesulfonamide 375.0 425

1,3-dimethyl-5-[5-methylsulfonyl-2- (oxolan-3-ylamino)phenyl]pyridine-2-one 363.1 426

1,3-dimethyl-5-[5-methylsulfonyl-2- (oxolan-3-yloxy)phenyl]pyridin-2-one364.0 427

1,3-dimethyl-5-[5- (methylsulfonylmethyl)-2-(2,2,2-trifluoroethoxy)phenyl]pyridin-2-one 390.0 428

5-[2-(cyclopropylmethylamino)-5- methylsulfonylphenyl]-1-ethyl-3-methylpyridin-2-one 361.1 429

5-[2-(2,4-difluorophenoxy)-5- (methylsulfonylmethyl)phenyl]-1-ethyl-3-methylpyridin-2-one 434.0 430

N-[3-(1,5-dimethyl-6-oxopyridin-3-yl)- 4-(4-trans-hydroxycyclohexyl)oxyphenyl]ethanesulfonamide 421.1 431

N-[3-(1,5-dimethyl-6-oxopyridin-3-yl)- 4-(4-cis-hydroxycyclohexyl)oxyphenyl]ethanesulfonamide 421.1 432

N-[4-(1-methyl-6-oxopyridin-3-yl)-5- (2-methylphenyl)thiophen-2-yl]ethanesulfonamide 389.1 433

N-[3-(1,5-dimethyl-6-oxopyridin-3-yl)- 4-(4-trans-hydroxycyclohexyl)oxyphenyl]methanesulfonamide 407.1 434

N-[3-(1,5-dimethyl-6-oxopyridin-3-yl)- 4-(4-cis-hydroxycyclohexyl)oxyphenyl]methanesulfonamide 407.1 435

N-[5-(2-ethylphenyl)-4-(1-methyl-6- oxopyridin-3-yl)thiophen-2-yl]ethanesulfonamide 403.1 436

1,3-dimethyl-5-[5-methylsulfonyl-2- (oxan-4-ylamino)phenyl]pyridin-2-one377.1 437

5-[2-(2,4-difluorophenoxy)-5- (methylsulfonylmethyl)phenyl]-3-fluoro-1-methylpyridin-2-one 424.1 438

5-[2-(cyclopropylmethylamino)-5- methylsulfonylphenyl]-3-(dimethyl-amino)-1-methylpyridin-2-one 376.2 439

N-[3-(1,5-dimethyl-6-oxopyridin-3-yl)- 4-(oxan-4-yloxy)phenyl]methanesulfonamide 393.1 440

5-[2-(cyclopropylmethylamino)-5- ethylsulfonylphenyl]-3-(dimethyl-amino)-1-methylpyridin-2-one 390.2 441

N-[3-(1,5-dimethyl-6-oxopyridin-3-yl)- 4-(oxan-4-yloxy)phenyl]ethanesulfonamide 407.1 442

N-[4-(2,4-difluorophenoxy)-3-(5- methoxy-1-methyl-6-oxopyridin-3-yl)phenyl]methanesulfonamide 437.1 443

N-[4-(2,4-difluorophenoxy)-3-(5- methoxy-1-methyl-6-oxopyridin-3-yl)phenyl]ethanesulfonamide 451.1 444

N-[3-(1,5-dimethyl-6-oxopyridin-3-yl)- 4-(oxolan-3-yloxy)phenyl]methanesulfonamide 379.0 445

N-[3-(1,5-dimethyl-6-oxopyridin-3-yl)- 4-(oxolan-3-yloxy)phenyl]ethanesulfonamide 393.2 446

N-[3-(1,5-dimethyl-6-oxopyridin-3-yl)- 4-(oxan-3-yloxy)phenyl]methanesulfonamide 393.1 447

N-[4-(4,4-difluorocyclohexyl)oxy-3- (1,5-dimethyl-6-oxopyridin-3-yl)phenyl]methanesulfonamide 427.1 448

N-[3-(1,5-dimethyl-6-oxopyridin-3-yl)- 4-(oxan-3-yloxy)phenyl]ethanesulfonamide 407.1 449

N-[4-(4,4-difluorocyclohexyl)oxy-3- (1,5-dimethyl-6-oxopyridin-3-yl)phenyl]ethanesulfonamide 441.1 450

5-[2-(cyclopropylmethoxy)-5- ethylsulfonylphenyl]-1,3-dimethylpyridin-2-one 362.1 451

N-[4-(2,4-difluorophenoxy)-3-(5- hydroxy-1-methyl-6-oxopyridin-3-yl)phenyl]ethanesulfonamide 437.0 452

4-(cyclopropylmethylamino)-3-(1,5- dimethyl-6-oxopyridin-3-yl)benzenesulfonamide 348.1 453

4-(cyclopropylmethylamino)-3-(1- methyl-6-oxopyridin-3-yl)benzenesulfonamide 334.1 454

5-[2-(2,4-difluorophenoxy)-5- (methylsulfonylmethyl)phenyl]-1,4-dimethylpyridin-2-one 420.0 455

5-[2-(2,4-difluorophenoxy)-5- (methylsulfonylmethyl)phenyl]-1,3-dimethylpyridin-2-one 420.1 456

5-(2-ethoxy-5-ethylsulfonylphenyl)-1- (²H₃)methyl-4-methylpyridin-2-one339.0 457

5-[2-(cyclopropylmethoxy)-5- ethylsulfonylphenyl]-1-(²H₃)methyl-4-methylpyridin-2-one 365.0 458

5-(2-ethoxy-5-ethylsulfonylphenyl)- 1,4-dimethylpyridin-2-one 336.1 459

5-[2-(cyclobutylmethoxy)-5- methylsulfonylphenyl]-1,3-dimethylpyridin-2-one 362.1 460

5-[2-(cyclobutylmethoxy)-5- methylsulfonylphenyl]-1- methylpyridin-2-one348.1 461

5-(5-ethylsulfonyl-2-methoxyphenyl)- 3-hydroxy-1-methylpyridin-2-one323.9 462

5-[2-(cyclopropylmethylamino)-5- methylsulfonylphenyl]-1,3-dimethylpyridin-2-one 347.1 463

N-[4-(2,4-difluorophenoxy)-3-[5- (dimethylamino)-1-methyl-6-oxopyridin-3-yl]phenyl] methanesulfonamide 450.1 464

N-[4-(2,4-difluorophenoxy)-3-[5- (dimethylamino)-1-methyl-6-oxopyridin-3-yl]phenyl] ethanesulfonamide 464.1 465

5-[2-(cyclopropylmethylamino)-5- ethylsulfonylphenyl]-1,3-dimethylpyridin-2-one 361.1 466

5-[2-(cyclopropylmethoxy)-5- ethylsulfonylphenyl]-1,4-dimethylpyridin-2-one 362.1 467

N-[3-(5-hydroxy-1-methyl-6- oxopyridin-3-yl)phenyl] methanesulfonamide295.0 468

5-[2-(cyclopropylmethylamino)-5- methylsulfonylphenyl]-1-methylpyridin-2-one 333.1 469

3-(dimethylamino)-5-(2-ethoxy-5- ethylsulfonylphenyl)-1-methyl-pyridin-2-one 365.1 470

5-[2-(2,4-difluorophenoxy)-5- (methylsulfonylmethyl)phenyl]-1-methylpyridin-2-one 406.0 471

N-[3-(1-methyl-6-oxo-5- phenylmethoxypyridin-3-yl)phenyl]methanesulfonamide 385.0 472

N-[4-(2,4-difluorophenoxy)-3-(1,5- dimethyl-6-oxopyridin-3-yl)phenyl]ethanesulfonamide 435.1 473

5-[2-(cyclopropylmethylamino)-5- ethylsulfonylphenyl]-1-methylpyridin-2-one 347.1 474

5-[2-(cyclopropylmethoxy)-5- methylsulfonylphenyl]-3-(dimethyl-amino)-1-methylpyridin-2-one 377.1 475

5-[4-fluoro-2-methoxy-5- (methylsulfonylmethyl)phenyl]-1-methylpyridin-2-one 326.0 476

5-[2-(cyclopropylmethoxy)-5- methylsulfonylphenyl]-1,3-dimethylpyridin-2-one 348.1 477

5-[2-(cyclopropylmethoxy)-5- methylsulfonylphenyl]-1,4-dimethylpyridin-2-one 348.1 478

N-[6-[3-(methanesulfonamido) phenyl]-4-methyl-3-oxopyrazin-2-yl]acetamide 337.0 479

N-[3-(1,4-dimethyl-6-oxopyridazin- 3-yl)phenyl]ethanesulfonamide 308.0480

N-[3-(1,5-dimethyl-6-oxopyridazin- 3-yl)phenyl]ethanesulfonamide 308.0481

N-[5-[3-(methanesulfonamido) phenyl]-1-methyl-2-oxopyridin-3-yl]propanamide 350.0 482

N-[5-[3-(methanesulfonamido) phenyl]-1-methyl-2-oxopyridin-3-yl]acetamide 336.0

Example 483:1-cyclobutyl-5-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-3-methylpyridin-2-oneStep 1: 1-cyclobutyl-3-methylpyridin-1-ium chloride

Cyclobutylamine (2.3 g, 32 mmol) was added to1-(2,4-dinitrophenyl)-3-methyl-pyridinium chloride (J. Org. Chem. 1997,62:729) (8.0 g, 31 mmol) in n-butanol (120 mL) at 20° C. and the deepred soln was refluxed overnight. Concentration under vacuum left aresidue that was treated with H₂O (20 mL) and the precipitate wasremoved by filtration, and the operation was repeated twice. Thecombined aq phase was basified with concentrated ammonia (2 mL) andwashed twice with EtOAc. Evaporation of the H₂O to gave the titlecompound (3.2 g, 70%) as a brown oil. LCMS: 148 M⁺.

Step 2: 1-cyclobutyl-3-methylpyridin-2-one

A stirred soln of the title compound from step 2 (2.8 g, 18.9 mmol) inH₂O (30 mL) was cooled to 5° C. and K₃Fe(CN)₆ in H₂O (30 mL) was addeddropwise over 1 hr. Then KOH (16.7 g, 298.6 mmol) in H₂O (5 mL) andtoluene (30 mL) were added, and the mixture was heated at 40° C. for 30min. The organic layer was separated, and the aq layer was extractedwith DCM. The combined organic layers were washed with H₂O, brine anddried over Na₂SO₄, filtered and concentrated. Silica gel chromatography(DCM) gave the title compound (1.9 g, 62%) as a yellow oil. LCMS: 164(M+H)⁺.

Step 3: 5-bromo-1-cyclobutyl-3-methylpyridin-2-one

The title compound of step 3 (1.5 g, 9.2 mmol) in acetic acid (30 mL)was stirred at room temp for 10 min. Bromine (1.51 g, 9.5 mmol) was thenadded slowly, and after about 2 hr, the mixture was diluted with H₂O andextracted with DCM. The organic soln was washed with H₂O, brine anddried over Na₂SO₄, filtered, concentrated and purified by silica gelchromatography (DCM) to give the title compound (2.0 g, 82%) as a yellowoil. LCMS: 242, 244 (M+H)⁺.

Step 4:1-cyclobutyl-5-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-3-methylpyridin-2-one

The title compound of step 4 (27 mg, 0.11 mmol), the title compound ofExample 90, step 1 (46 mg, 0.13 mmol), K₂CO₃ (46 mg, 0.33 mmol) andPd(dppf)₂Cl₂ (8 mg, 0.011 mmol) in DMF (2 mL) was N₂ purged andmicrowaved at 100° C. After 2 hr, the mixture was concentrated undervacuum and DCM was added, then washed with H₂O, brine and dried overNa₂SO₄. Purification by preparative TLC gave the title compound (25 mg,58%) as a white solid. ¹H NMR (CDCl₃, 400 MHz): δ 7.85-7.81 (m, 2H),7.79 (d, J=1.6 Hz, 1H), 7.47 (s, 1H), 7.02 (d, J=8.4 Hz, 1H), 5.27-5.23(m, 1H), 3.94 (d, J=8.0 Hz, 2H), 3.07 (s, 3H), 2.57-2.50 (m, 2H),2.32-2.24 (m, 2H), 2.21 (s, 3H), 1.93-1.84 (m, 2H), 1.31-1.25 (m, 1H),0.70-0.65 (m, 2H), 0.40-0.36 (m, 2H). LCMS: 388 (M+H)⁺.

Example 484:N-[3-(1-cyclobutyl-5-methyl-6-oxopyridin-3-yl)-4-(2,4-difluorophenoxy)phenyl]methanesulfonamide

The title compound of Example 483, step 3 (27 mg, 0.11 mmol),N-[4-(2,4-difluoro-phenoxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanesulfonamide(55 mg, 0.13 mmol), K₂CO₃ (46 mg, 0.33 mmol) and Pd(dppf)₂Cl₂ (8 mg,0.011 mmol) in DMF (2 mL) were reacted and purified in a manner similarto Example 483, step 4 to give the title compound (16 mg, 32%) as awhite solid. ¹H NMR (CDCl₃, 400 MHz): δ 7.65 (s, 1H), 7.42 (s, 1H),7.26-7.27 (m, 1H), 7.13 (dd, J=8.8, 2.8 Hz, 1H), 6.97-6.89 (m, 2H), 6.83(d, J=9.2 Hz, 2H), 6.54 (s, 1H), 5.09-5.18 (m, 1H), 3.04 (s, 3H),2.53-2.46 (m, 2H), 2.23-2.18 (m, 2H), 2.16 (s, 3H), 1.87-1.81 (m, 2H).LCMS: 461 (M+H)⁺.

Example 485:1-benzyl-5-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-3-methylpyridin-2-one

The title compound was prepared in a manner similar to Example 483,steps 1-4 except that benzylamine was substituted for cyclobutylamine instep 1. ¹H NMR (CDCl₃, 400 MHz): δ 7.79 (s, 1H), 7.62 (d, J=2.8 Hz, 1H),7.49-7.51 (m, 1H), 7.34-7.38 (m, 4H), 7.29-7.32 (m, 2H), 6.98 (d, J=8.8Hz, 1H), 5.20 (s, 2H), 3.89-3.94 (m, 2H), 3.04 (s, 3H), 2.22 (s, 3H),1.13-1.18 (m, 1H), 0.58-0.62 (m, 2H), 0.28-0.34 (m, 2H). LCMS: 424(M+H)⁺.

Example 486:1,3-dimethyl-5-(2-methyl-5-methylsulfonyl-2,3-dihydro-1-benzofuran-7-yl)pyridine-2-oneStep 1: 2-methyl-5-methylsulfonyl-2,3-dihydro-1-benzofuran

A mixture of 5-bromo-2-methyl-2,3-dihydro-1-benzofuran (1.0 g, 4.72mmol), CH₃SO₂Na (730 mg, 7.08 mmol), L-proline (110 mg, 0.94 mmol),K₂CO₃ (120 mg, 0.94 mmol) and CuI (89 mg, 0.47 mmol) in DMSO (10 mL) wasirradiated at 140° C. for 2 hr under microwave. The mixture wasextracted with EtOAc (2×30 mL). The combined organic layers were washedwith brine (30 mL), dried over Na₂SO₄, filtered, and concentrated togive the crude product that was purified by CC on silica gel (PE:EA=2:1)to give the title compound (500 mg, 50%). ¹H NMR (CDCl₃, 400 MHz) δ7.71-7.70 (m, 2H), 6.86-6.82 (m, 1H), 5.08-5.03 (m, 1H), 3.41-3.35 (m,1H), 3.02 (s, 3H), 2.89-2.83 (m, 1H), 1.56 (d, J=6.4 Hz, 3H).

Step 2: 7-bromo-2-methyl-5-methylsulfonyl-2,3-dihydro-1-benzofuran

To a mixture of the title compound from Step 1 (300 mg, 1.42 mmol) inDCM (10 mL) was added Fe (159 mg, 2.84 mmol) and Br₂ (454 mg, 2.84 mmol)in one portion under N₂. The mixture was stirred at room temp for 6 hr.The rxn mixture was washed with satd aq Na₂SO₃ (200 mL) and extractedwith DCM (30 mL×2). The combined organic layers were washed with brine(20 mL×2), dried with anhydrous Na₂SO₄, filtered, and concentrated underreduced pressure. The residue was purified by CC (PE:EA=3:1) to give thetitle compound (300 mg, 73%) as a yellow solid. ¹H NMR (CDCl₃, 400 MHz):δ 7.90 (d, J=1.6 Hz, 1H), 7.64 (d, J=1.6 Hz, 1H), 5.20-5.14 (m, 1H),3.53-3.47 (m, 1H), 3.01-2.95 (m, 1H), 3.04 (s, 3H), 1.56 (d, J=6.4 Hz,3H). LCMS: 291.0 (M+1)⁺; 293.0.

Step 3:1,3-dimethyl-5-(2-methyl-5-methylsulfonyl-2,3-dihydro-1-benzofuran-7-yl)pyridin-2-one

A soln of the title compound in Step 2 (300 mg, 1.03 mmol),1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one(309 mg, 1.24 mmol), Pd(dppf)Cl₂ (76 mg, 0.103 mmol), Na₂CO₃ (328 mg,3.09 mmol) in dioxane (8 mL) and H₂O (1 mL) was stirred at 80° C. underN₂ for 16 hr. The solvent was removed under reduced pressure to give aresidue that was purified by CC (PE:EA=1:2) to give the title compound(60.0 mg, 18%) as a yellow solid. ¹H NMR (DMSO-d6, 400 MHz): δ 8.02 (s,1H), 7.76 (s, 1H), 7.74 (s, 1H), 7.66 (s, 1H), 5.15-5.13 (m, 1H), 3.51(s, 3H), 3.49-3.42 (m, 1H), 3.19 (s, 3H), 2.94-2.88 (m, 1H), 2.07 (s,3H), 1.44 (d, J=5.2 Hz, 3H). LCMS: 334.1 (M+1)⁺.

Example 487:4-[5-(ethylsulfonylmethyl)-2-(2,2,2-trifluoroethoxy)phenyl]-2-methylisoquinolin-1-oneStep 1: methyl 3-bromo-4-(2,2,2-trifluoroethoxy)benzoate

To a soln of methyl 3-bromo-4-fluorobenzoate (100 mg, 0.43 mmol) in DMFwas added 2,2,2-trifluoroethanol (52 mg, 0.52 mmol), K₂CO₃ (119 mg, 0.86mmol), and the mixture was stirred at 60° C. for 2 hr. The mixture wascooled and H₂O (50 mL) was added. The aq layer was extracted with EtOAc(30 mL×3). The combined organic layers were washed with H₂O (30 mL×3),brine (30 mL), dried over anhydrous Na₂SO₄, filtered, concentrated, andpurified by chromatog. (PE:EA=20:1) to afford compound 3 (95 mg, 88%) asa white solid. ¹H NMR (CDCl₃, 400 MHz) δ 8.29 (d, J=2.0 Hz, 1H), 8.00(dd, J₁=8.4 Hz, J₂=2.0 Hz, 1H), 6.93 (d, J=8.4 Hz, 1H), 4.48 (q, J=8.0Hz, 2H), 3.92 (s, 3H). LCMS: 313.0 (M+1)⁺.

Step 2: [3-bromo-4-(2,2,2-trifluoroethoxy)phenyl]methanol

To soln of the title compound from Step 1 (2.00 g, 5.85 mmol) in THF(20.0 mL) was added LiAlH₄ (0.18 g, 4.68 mmol) in several portions at−40° C. The mixture was kept at −40° C. and stirred for 45 min. The rxnwas quenched with H₂O (0.2 mL), 15% NaOH aq (0.2 mL) and additional H₂O(0.6 mL), and the mixture stirred at room temp for 15 min, then driedover Na₂SO₄, and filtered. The filtrate was concentrated and the residuepurified by silica gel chromatography (PE:EA=5:1 to 3:1) to give thetitle compound (1.62 g, 89%) as a white solid. ¹H NMR (DMSO-d₆, 400MHz): δ 7.55 (d, J=2.0 Hz, 1H), 7.31-7.28 (m, 1H), 7.19 (d, J=8.4 Hz,1H), 4.83 (q, J=8.8 Hz, 2H), 4.44 (s, 2H).

Step 3: 2-bromo-4-(chloromethyl)-1-(2,2,2-trifluoroethoxy)benzene

A soln of the title compound from Step 2 (300 mg, 1.05 mmol) in DCM (10mL) was cooled to 0° C. and treated with triethylamine (91 mg, 1.15mmol) and methanesulfonyl chloride (142 mg, 1.25 mmol). The rxn mixturewas warmed to room temp and stirred overnight. It was then diluted withDCM (10 mL) and washed with 1M HCl (10 mL) and sat. NaHCO₃ (10 mL). Theorganic phase was dried over Na₂SO₄, filtered and conc under reducedpress. The crude residue was purified by silica gel chromatography toafford the title compound (260 mg, 82%) as a white solid. ¹H NMR (CDCl3,400 MHz): δ 7.63 (d, J=2.0 Hz, 1H), 7.32 (dd, J₁=8.4 Hz, J₂=2.0 Hz, 1H),6.92 (d, J=8.4 Hz, 1H), 4.53 (s, 2H), 4.42 (q, J=8.0 Hz, 2H).

Step 4: 2-bromo-4-(ethylsulfanylmethyl)-1-(2,2,2-trifluoroethoxy)benzene

To a soln of the title compound from Step 3 (2.00 g, 6.59 mmol) in DCM(200 mL) was added TEA (1 g, 9.89 mmol), NaI (898 mg, 5.99 mmol) andEtSH (613 mg, 9.89 mmol). The mixture was stirred at 30° C. for 4 hr.The rxn was poured into H₂O (10 mL) and extracted with EtOAc (10 mL×3).The combined organic layers were washed with brine (30 mL), dried overanhydr. Na₂SO₄ and filtered. Solvents were removed under reducedpressure and the residue was purified by chromatography (PE:EA=1:0 to3:1) to give the title compound (2.1 g, 96.8%) as a white solid. ¹H NMR(CDCl₃, 400 MHz): δ 7.55 (d, J=2.0 Hz, 1H), 7.24 (dd, J₁=8.4 Hz, J₂=2.0Hz, 1H), 6.89 (d, J=8.4 Hz, 1H), 4.42 (q, J=8.0 Hz, 2H), 3.66 (s, 2H),2.47-2.41 (m, 2H), 1.26-1.22 (m, 3H).

Step 5: 2-bromo-4-(ethylsulfonylmethyl)-1-(2,2,2-trifluoroethoxy)benzene

To a soln of the title compound from Step 4 (2.10 g, 6.38 mmol) in DCM(210 mL) was added MCPBA (4.41 g, 25.53 mmol) in several portions. Themixture was stirred at 25° C. for 12 hr. The rxn was poured into sat. aqNa₂SO₃ (100 mL) and extracted with DCM (80 mL×3). The combined organiclayers were washed with sat. NaHCO₃ (100 mL×2) and brine (100 mL), driedover anhydrous Na₂SO₄, filtered and concentrated under reduced pressure.The residue was purified by silica gel chromatography (PE:EA=1:0-2:1) togive the title compound (2.10 g, 91%) as a white solid. ¹H NMR (CDCl3,400 MHz) δ 7.64 (d, J=2.0 Hz, 1H), 7.37 (dd, J₁=8.4 Hz, J₂=2.4 Hz, 1H),6.95 (d, J=8.4 Hz, 1H), 4.43 (q, J=8.0 Hz, 2H), 4.15 (s, 2H), 2.91 (q,J=7.6 Hz, 2H), 1.39 (t, J=7.6 Hz, 3H).

Step 6:4-[5-(ethylsulfonylmethyl)-2-(2,2,2-trifluoroethoxy)phenyl]-2-methylisoquinolin-1-one

The title compound from Step 5 (200 mg, 0.58 mmol),2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1-one(197 mg, 0.69 mmol), Pd(PPh₃)₄ (67 mg, 58.0 umol) and Na₂CO₃ (184 mg,1.74 mmol) in dioxane (6 mL) and H₂O (6 drops) was degassed and thenheated to 70° C. for 18 hr under N₂. The rxn mixture was concentratedunder reduced pressure and the residue was purified by CC (PE:EA=5:1 to1:1) followed by prep-HPLC purification to afford the title compound(164.44 mg, 67%) as an off-white solid. ¹H NMR (CDCl₃, 400 MHz): δ 8.52(d, J=8.0 Hz, 1H), 7.58-7.48 (m, 3H), 7.40 (d, J=2.4 Hz, 1H), 7.22 (d,J=8.0, 1H), 7.07 (t, J=8.0, 2H), 4.30 (q, J=8.0 Hz, 2H), 4.23 (s, 2H),3.67 (s, 3H), 2.98 (q, J=7.6 Hz, 2H), 1.43 (t, J=7.6 Hz, 3H). LCMS:440.0 (M+1)⁺.

Example 488:2-methyl-4-[5-(methylsulfonylmethyl)-2-(2,2,2-trifluoroethoxy)phenyl]isoquinolin-1-oneStep 1:2-bromo-4-(methylsulfanylmethyl)-1-(2,2,2-trifluoroethoxy)benzene

The title compound was prepared in a manner similar to Example 487 Step4, by substituting methanethiol for ethanethiol. ¹H NMR (CDCl3, 400MHz): δ 7.56 (d, J=2.0 Hz, 1H), 7.25 (dd, J₁=8.4 Hz, J₂=2.0 Hz, 1H),6.93-6.90 (m, 1H), 4.44-4.35 (m, 2H), 3.63 (s, 2H), 2.02 (s, 3H).

Step 2:2-bromo-4-(methylsulfonylmethyl)-1-(2,2,2-trifluoroethoxy)benzene

The title compound was prepared in a manner similar to Example 487 Step5, by substituting2-bromo-4-(methylsulfanylmethyl)-1-(2,2,2-trifluoroethoxy)benzene for2-bromo-4-(ethylsulfanylmethyl)-1-(2,2,2-trifluoroethoxy)benzene. ¹H NMR(CDCl3, 400 MHz): δ 7.65 (d, J=2.0 Hz, 1H), 7.38 (dd, J₁=8.4 Hz, J₂=2.4Hz, 1H), 7.12-7.06 (m, 1H), 4.43 (q, J=8.0 Hz, 2H), 4.19 (s, 2H), 2.82(s, 3H).

Step 3:2-methyl-4-[5-(methylsulfonylmethyl)-2-(2,2,2-trifluoroethoxy)phenyl]isoquinolin-1-one

The title compound was prepared in a manner similar to Example 487 Step6, by substituting2-bromo-4-(methylsulfonylmethyl)-1-(2,2,2-trifluoroethoxy)benzene for2-bromo-4-(ethylsulfonylmethyl)-1-(2,2,2-trifluoroethoxy)benzene. ¹H NMR(CDCl3, 400 MHz): δ 8.52 (d, J=8.0 Hz, 1H), 7.60-7.49 (m, 3H), 7.41 (d,J=2.0 Hz, 1H), 7.22 (d, J=8.0, 1H), 7.08-7.06 (m, 2H), 4.33-4.27 (m,4H), 3.67 (s, 3H), 2.87 (s, 3H). LCMS: 426.0 (M+1)⁺.

Example 489:1,3-dimethyl-5-(7-methylsulfonyl-2,3-dihydro-1,4-benzodioxin-5-yl)pyridin-2-oneStep 1: 3,4-dihydro-2H-chromen-2-ylmethanol

A mixture of 4-oxochromene-2-carboxylic acid (20.0 g, 105 mmol) and Pd/C(3.0 g, 10% (w/w)) in AcOH (200 mL) was placed in Parr hydrogenationapparatus under H₂ (50 psi) and stirred for 25 hr at room temp. It wasthen filtered and concentrated. The residue was suspended in H₂O (300mL), stirred for 10 min, filtered and dried to give3,4-dihydro-2H-chromene-2-carboxylic acid (13.5 g, 72%) as a whitesolid. BH₃ (57 mL, 114 mmol, 2.0 M in THF) was added slowly to a soln ofthis carboxylic acid in THF (120 mL) at 0° C. The rxn mixture was thenwarmed to room temp and stirred for 5 hr at this temp. THF:H₂O (30 mL,1:1) was added drop-wise while keeping the temp between 0-5° C. andstirred for 20 min. K₂CO₃ (26.0 g, 189 mmol) was added and the rxn wasvigorously stirred for 30 min. The THF layer was separated andconcentrated to give the title compound (11.0 g, 89%) as a brown oil. ¹HNMR (400 MHz, CDCl₃): δ 7.10-7.03 (m, 2H), 6.86-6.81 (m, 2H), 4.14-4.08(m, 1H), 3.85-3.68 (m, 2H), 2.92-2.84 (m, 1H), 2.80-2.73 (m, 1H),1.98-1.92 (m, 1H), 1.90-1.79 (m, 1H). LCMS: 165 (M+1)⁺.

Step 2: 3,4-dihydro-2H-chromen-2-ylmethyl trifluoromethanesulfonate

Trifluoromethanesulfonic anhydride (19.6 g, 69.5 mmol) in DCM (15 mL)was added to a soln of the title compound from Step 1 (9.50 g, 57.9mmol) in DCM (100 mL) and pyridine (11.0 g, 139 mmol) cooled to −5° C.The rxn was then stirred at 0° C. for 1 hr. H₂O (150 mL) was added andthe rxn was extracted with DCM (150 mL). The organic layer was washedwith 1M HCl (180 mL), H₂O (100 mL), and NaHCO₃ (100 mL aq). The organicphase was dried over Na₂SO₄, filtered and concentrated to give the titlecompound (13.5 g, 79%) as a pale-brown oil. ¹H NMR (400 MHz, CDCl₃): δ7.12-7.04 (m, 2H), 6.90-6.83 (m, 2H), 4.66-4.61 (m, 2H), 4.36-4.31 (m,1H), 2.96-2.79 (m, 2H), 2.09-2.03 (m, 1H), 1.95-1.84 (m, 1H). LCMS: 314(M+NH₄)⁺.

Step 3: 2-ethyl-3,4-dihydro-2H-chromene

MeMgBr (45.6 mL, 137 mmol, 3M in ether) was added to a mixture of thetitle compound from Step 2 (13.5 g, 45.6 mmol) and CuBr-Me₂S (1.61 g,7.74 mmol) in THF (150 mL) at −5° C. The rxn was stirred at room tempfor 2 hr. It was then poured onto a soln of NH₄Cl (55 g, 1.04 mol) inH₂O (200 mL) and extracted with DCM (3×150 mL). The organic layer wasdried over Na₂SO₄, filtered and concentrated under reduced pressure togive the title compound (6.66 g, 90%) as a brown oil. ¹H NMR (400 MHz,CDCl₃): δ 7.09-7.02 (m, 2H), 6.82-6.78 (m, 2H), 3.93-3.87 (m, 1H),2.84-2.72 (m, 2H), 2.02-1.96 (m, 1H), 1.81-1.61 (m, 3H), 1.04 (t, J=7.2Hz, 3H).

Step 4: 2-ethyl-6-nitro-3,4-dihydro-2H-chromene and2-ethyl-8-nitro-3,4-dihydro-2H-chromene

The title compound from Step 3 (1.0 g, 6.17 mmol) was added to HNO₃ (5mL, 65-68%) at 0° C., warmed to room temp and stirred for 1 hr. It wasthen poured onto an ice-water mixture, extracted with EtOAc (50 mL),dried over Na₂SO₄ and concentrated under reduced pressure. The residuewas purified by silica gel CC (PE:EA 100:1 to 50:1) to give a mixture ofthe title compounds (600 mg) which was used in the next step.

Step 5: N-(2-ethyl-3,4-dihydro-2H-chromen-6-yl)methanesulfonamide

The mixture of the title compounds from Step 4 (600 mg) was suspended inMeOH (6 mL) and sat. NH₄Cl soln (2 mL). Fe (810 mg, 14.5 mmol) was addedand the mixture heated to 85° C. for 2.5 hr. It was then filtered andextracted with EtOAc. The organic layer was dried and conc under reducedpress. to give a crude mixture of 2-ethyl-3,4-dihydro-2H-chromen-6-amineand 2-ethyl-3,4-dihydro-2H-chromen-8-amine. This mixture was dissolvedin DCM (10 mL), then TEA (0.8 mL) and methanesulfonyl chloride (400 mg,3.50 mmol) added; this was stirred at room temp for 1 hr; then extractedwith DCM (45 mL×2), dried over Na₂SO₄, filtered, concentrated underreduced pressure, and purified by CC (PE:E A=50:1 to 20:1 to 10:1) togive the title compound (190 mg, 12% for three steps) as a yellow solid.¹H NMR (300 MHz, CDCl₃): δ 6.99-6.80 (m, 2H), 6.78 (d, J=8.7 Hz, 1H),6.16 (s, 1H), 3.95-3.90 (m, 1H), 2.96 (s, 3H), 2.83-2.76 (m, 2H),2.04-1.97 (m, 1H), 1.81-1.64 (m, 3H), 1.05 (t, J=7.2 Hz, 3H). LCMS: 273(M+NH₄)⁺.

Step 6:N-(8-bromo-2-ethyl-3,4-dihydro-2H-chromen-6-yl)methanesulfonamide

To a soln of the title compound from Step 5 (170 mg, 0.667 mmol) in ACN(6 mL) was added NBS (156 mg, 0.867 mmol). The mixture was stirred for 7hr at room temp; then extracted with DCM, dried over Na₂SO₄, filtered,and conc under reduced press. The residue was purified with prep-TLC(PE:EA 3:1) to give the title compound (105 mg, 47%) as a gray solid. ¹HNMR (400 MHz, CDCl₃): δ 7.23 (d, J=2.4 Hz, 1H), 6.96 (d, J=2.4 Hz, 1H),6.24 (s, 1H), 4.01-3.99 (m, 1H), 2.97 (s, 3H), 2.84-2.77 (m, 2H),2.04-1.99 (m, 1H), 1.85-1.66 (m, 3H), 1.09 (t, J=7.2 Hz, 3H).

Step 7:N-[2-ethyl-8-(2-methyl-1-oxoisoquinolin-4-yl)-3,4-dihydro-2H-chromen-6-yl]methanesulfonamide

A mixture of the title compound from Step 6 (105 mg, 0.315 mmol),2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1-one(108 mg, 0.379 mmol), K₂CO₃ (131 mg, 0.949 mmol) and Pd(dppf)Cl₂ (23.1mg, 0.032 mmol) in dioxane/H₂O (10 mL/3 mL) was heated to 85° C. for 2hr, then filtered and extracted with EtOAc. The organic layer was concunder reduced press. The residue was purified by CC (PE:EA 50:1 to 20:1to 10:1) to give the title compound (25 mg, 19%). ¹H NMR (400 MHz,CD₃OD): δ 8.31 (d, J=8.4 Hz, 1H), 7.59-7.55 (m, 1H), 7.47-7.43 (m, 1H),7.31-7.23 (m, 2H), 7.05 (s, 1H), 6.95 (d, J=2.8 Hz, 1H), 3.77-3.71 (m,1H), 3.60 (s, 3H), 2.95-2.75 (m, 5H), 1.95-1.92 (m, 1H), 1.66-1.54 (m,1H), 1.38-1.22 (m, 2H), 0.59-0.55 (m, 1.25H), 0.42-0.38 (m, 1.75H).LCMS: 413.0 (M+1)⁺.

Example 491:N-[2-ethyl-8-(2-methyl-1-oxoisoquinolin-4-yl)-3,4-dihydro-2H-chromen-6-yl]ethanesulfonamide

The title compound was prepared in a manner similar to Example 490 bysubstituting ethanesulfonyl chloride for methanesulfonyl chloride inStep 5. ¹H NMR (400 MHz, CD₃OD): δ 8.39 (d, J=7.6 Hz, 1H), 7.67-7.63 (m,1H), 7.56-7.52 (m, 1H), 7.37-7.30 (m, 2H), 7.12 (s, 1H), 7.03 (d, J=2.8Hz, 1H), 3.86-3.81 (m, 1H), 3.69 (s, 3H), 3.10 (q, J=7.2 Hz, 2H),3.02-2.81 (m, 2H), 2.03-1.99 (m, 1H), 1.75-1.41 (m, 3H), 1.36 (t, J=7.6Hz, 3H), 0.67-0.62 (m, 1.25H), 0.51-0.48 (m, 1.75H). LCMS: 427.0 (M+1)⁺.

Example 492:N-[8-(1,5-dimethyl-6-oxopyridin-3-yl)-2-ethyl-3,4-dihydro-2H-chromen-6-yl]ethanesulfonamide

The title compound was prepared in a manner similar to Example 491 bysubstituting1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-onefor2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1-one.¹H NMR (400 MHz, CD₃OD): δ 7.69 (s, 1H), 7.66 (s, 1H), 7.02 (m, 1H), 7.0(s, 1H), 3.96-3.93 (m, 1H), 3.65 (s, 3H), 3.07 (q, J=7.5 Hz, 2H),2.93-2.82 (m, 2H), 2.18 (s, 3H), 2.08-2.04 (m, 1H), 1.72-1.66 (m, 3H),1.34 (t, J=7.6 Hz, 3H), 1.04 (t, J=7.2 Hz, 3H). LCMS: 391.0 (M+1)⁺.

Example 493:4-(2-cyclopropyl-5-methylsulfonyl-2,3-dihydro-1-benzofuran-7-yl)-2-methylisoquinolin-1-oneStep 1: 7-bromo-2-cyclopropyl-5-methylsulfonyl-1-benzofuran

To a soln of 2,6-dibromo-4-methylsulfonylphenol (1 g, 3.30 mmol) inpyridine (40 mL) was added ethynylcyclopropane (240 mg, 3.64 mmol) andCu₂O (260 mg, 1.82 mmol). The rxn mixture was degassed with N₂. Themixture was heated to 130° C. for 3 hr. It was then concentrated andpurified by CC (PE to PE/EA=3/1) to give the title product (510 mg, 53%)as a gray solid. ¹H NMR (CDCl₃, 400 MHz) δ 7.99 (s, 1H), 7.93 (s, 1H),6.52 (s, 1H), 3.07 (s, 3H), 2.13-2.11 (m, 1H), 1.13-1.05 (m, 4H).

Step 2: 7-bromo-2-cyclopropyl-5-methylsulfonyl-2,3-dihydro-1-benzofuran

To a soln of the title compound from Step 1 (250 mg, 0.79 mmol) inEt₃SiH (516 mg, 4.44 mmol) at 0° C. was added TFA (5.43 g, 47.59 mmol)in one portion. The rxn mixture was warmed up to room temp and stirredfor 48 hr. Aq NaOH soln (10 mL, 1N) was added slowly to the above soln.The mixture was extracted with EtOAc (10 mL). The organic layer wasdried over Na₂SO₄, filtered and concentrated. The residue was purifiedby CC (PE to PE/EA=2/1) to give the title compound (83 mg, 33%) as awhite solid. ¹H NMR (CDCl₃, 400 MHz) δ 7.90 (s, 1H), 7.64 (s, 1H),4.47-4.43 (m, 1H), 3.51-3.47 (m, 1H), 3.23-3.17 (m, 1H), 3.04 (s, 3H),1.24-1.22 (m, 1H), 0.74-0.55 (m, 3H), 0.44-0.41 (m, 1H).

Step 3:4-(2-cyclopropyl-5-methylsulfonyl-2,3-dihydro-1-benzofuran-7-yl)-2-methylisoquinolin-1-one

Example 494:4-(2-ethyl-5-methylsulfonyl-2,3-dihydro-1-benzofuran-7-yl)-2-methylisoquinolin-1-oneStep 1: 2-ethyl-7-iodo-5-methylsulfonyl-1-benzofuran

To a soln of 2,6-diiodo-4-methylsulfonylphenol (1.00 g, 2.36 mmol) inpyridine (10 mL) at 25° C. was added but-1-yne (128 mg, 2.36 mmol) andCu₂O (135 mg, 0.944 mmol). The mixture was stirred at 130° C. for 3 hrunder a N₂, then cooled to 25° C., diluted with 1N HCl (200 ml) andextracted with EtOAc (30 mL×2). The combined organic layers were washedby brine (100 mL), dried over Na₂SO₄, filtered and concentrated. Theresidue was purified by CC (PE:EA=10:1 to 5:1) to afford the titlecompound (400 mg, 48%) as a solid. ¹H NMR (CDCl₃, 400 MHz): δ 8.14 (d,J=1.6 Hz, 1H), 8.06 (d, J=1.6 Hz, 1H), 6.62 (s, 1H), 3.09 (s, 3H), 2.90(q, J=7.6 Hz, 2H), 1.38 (t, J=7.6 Hz, 3H). LCMS: 350.9 (M+H⁺).

Step 2:4-(2-ethyl-5-methylsulfonyl-1-benzofuran-7-yl)-2-methylisoquinolin-1-one

To a soln of2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1-one(82 mg, 286 μmol) and the title compound from Step 1 (100 mg, 286 μmol)in H₂O (2 mL) and dioxane (20 mL) was added Pd(dppf)Cl₂ (21 mg, 28.6μmol, 0.10 Eq) and Na₂CO₃ (61 mg, 572 μmol). The mixture was degassedwith N₂ and heated to 90° C. for 4 hr; then cooled to room temp andconcentrated under reduced pressure. The residue was purified by CC(PE:EA 3:1 to 1:1) followed by prep-HPLC to afford the title compound(35.57 mg, 33%) as a white solid. ¹H NMR (CDCl₃, 400 MHz): δ 8.56 (d,J=7.2 Hz, 1H), 8.19 (d, J=1.6 Hz, 1H), 7.83 (d, J=1.6 Hz, 1H), 7.60-7.57(m, 2H), 7.29-7.27 (m, 2H), 6.60 (s, 1H), 3.73 (s, 3H), 3.15 (s, 3H)2.75 (q, J=7.2 Hz, 2H), 1.28 (t, J=7.2 Hz, 3H). LCMS: 382.0 (M+H⁺).

Step 3:4-(2-ethyl-5-methylsulfonyl-2,3-dihydro-1-benzofuran-7-yl)-2-methylisoquinolin-1-one

To a soln of the title compound from Step 2 (130 mg, 340 umol) in MeOH(3 mL) was added Pd/C (70 mg, 10% w/w) in one portion. The rxn mixturewas stirred at 25° C. under H₂ atmosphere (15 psi) for 8 hr; thenfiltered through celite. The solvent was removed under reduced pressureand the residue purified by prep-HPLC to give the title compound (12.4mg) as a gray solid. ¹H NMR (CDCl₃, 300 MHz): δ 8.54-8.51 (d, J=7.5 Hz,1H), 7.79-7.75 (m, 2H), 7.75-7.54 (m, 2H), 7.32-7.29 (d, J=8.1 Hz, 1H),7.16 (s, 1H), 4.90-4.85 (m, 1H), 3.69 (s, 3H), 3.49-3.41 (m, 1H),3.06-3.00 (m, 1H), 1.85-1.70 (m, 2H), 0.96-0.91 (t, J=7.5 Hz, 3H). LCMS:384.0 (M+1).

Example 495:N-[7-(1,5-dimethyl-6-oxopyridin-3-yl)-2-propyl-2,3-dihydro-1-benzofuran-5-yl]ethanesulfonamideStep 1: 2-cyclopropyl-7-iodo-5-nitro-1-benzofuran

A soln of 2,6-diiodo-4-nitrophenol (10 g, 25.6 mmol),ethynylcyclopropane (1.9 g, 28.8 mmol) and Cu₂O (1.9 mg, 13.2 mmol) in100 mL of dry pyridine was refluxed for 2 hr. The rxn mixture was pouredinto 1 L of H₂O and stirred for 10 min. The resulting mixture wasfiltered. The cake was purified by CC on silica gel eluting withEtOAc:PE (0% to 20%) to give the title compound (6.6 g, 78% yield) as ayellow solid. ¹H NMR (CDCl₃, 400 MHz): δ 8.47 (d, J=2.4 Hz, 1H), 8.32(d, J=2.4 Hz, 1H), 6.58 (s, 1H), 2.13-2.07 (m, 1H), 1.14-1.04 (m, 4H).

Step 2: 2-cyclopropyl-7-iodo-1-benzofuran-5-amine

To a soln of the title compound from Step 1 (2.0 g, 6.0 mmol) and Fe(1.0 g, 18 mmol) in MeOH (80 mL) was added sat. NH₄Cl soln (10 mL). Therxn mixture was refluxed for 1 hr. The mixture was cooled to room tempand poured into 400 mL of DCM. The resulting mixture was filtered andthe filtrate was washed with H₂O (100 mL) and brine. The organic layerwas dried over anhydrous Na₂SO₄, filtered and concentrated under reducedpressure to give the crude title compound (1.5 g, 83% yield) as red oilthat was used for the next step directly. ¹H NMR (CDCl₃, 400 MHz): δ6.87 (d, J=2.4 Hz, 1H), 6.61 (d, J=2.0 Hz, 1H), 6.19 (s, 1H), 3.45 (br,2H), 1.97-1.90 (m, 1H), 0.95-0.85 (m, 4H). LCMS: 300 (M+1)⁺.

Step 3: N-(2-cyclopropyl-7-iodo-1-benzofuran-5-yl)ethanesulfonamide

To a soln of the title compound from Step 2 (1.0 g, 3.3 mmol) in 20 mLof dry DCM was added a soln of pyridine (793 mg, 10 mmol) in DCM (10mL), followed by addition of EtSO₂Cl (473 mg, 3.7 mmol). The rxn mixturewas stirred at room temp for 1 hr, then diluted with DCM (20 mL), andwashed with H₂O (20 mL×2) and brine. The organic layer was dried overNa₂SO₄, filtered and concentrated under reduced pressure to give thecrude title compound (1.3 g, 100% yield) that was used directly in thenext step. ¹H NMR (CDCl₃, 400 MHz): δ 7.42 (d, J=2.0 Hz, 1H), 7.38 (d,J=2.0 Hz, 1H), 6.88 (br, 1H), 6.40 (s, 1H), 3.09 (q, J=7.2 Hz, 2H), 1.37(t, J=7.2 Hz, 3H), 2.04-2.08 (m, 1H), 1.06-0.97 (m, 4H). LCMS: 409(M+18)⁺.

Step 4:N-[2-cyclopropyl-7-(1,5-dimethyl-6-oxopyridin-3-yl)-1-benzofuran-5-yl]ethanesulfonamide

To a soln of the title compound from Step 3 (500 mg, 1.3 mmol) and1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one(380 mg, 1.5 mmol) in 10 mL of DMF was added K₂CO₃ (50 mg, 3.8 mmol),H₂O (2 mL) and Pd(dppf)Cl₂ (30 mg) under N₂. The rxn mixture was heatedto 100° C. for 1 hr, and the resulting mixture poured into 100 mL of H₂Othen extracted with DCM (100 mL×2). The combined organic layers weredried over anhydrous Na₂SO₄, filtered and concentrated under reducedpressure. The residue was purified by CC on silica gel eluting withEtOAc to give the title compound (230 mg, 47% yield) as a white solid.¹H NMR (CDCl₃, 400 MHz): δ 7.81 (d, J=3.6 Hz, 1H), 7.67-7.66 (m, 1H),7.26 (t, J=1.2 Hz, 1H), 7.12 (d, J=3.2 Hz, 1H), 6.54 (br, 1H), 6.36 (d,J=0.8 Hz, 1H), 3.67 (s, 3H), 3.14-3.06 (m, 2H), 2.25 (s, 3H), 2.11-2.00(m, 1H), 1.38-1.43 (m, 3H), 1.09-0.92 (m, 4H). LCMS: 387 (M+1)⁺.

Step 5:N-[7-(1,5-dimethyl-6-oxopyridin-3-yl)-2-propyl-2,3-dihydro-1-benzofuran-5-yl]ethanesulfonamide

A mixture of the title compound from Step 4 (70 mg, 0.18 mmol) and 10 mgof Pd/C in 40 mL MeOH was stirred under a H₂ atmosphere at room temp for1 hr. The resulting mixture was filtered and the filtrate wasconcentrated under reduced pressure. The residue was purified byprep-HPLC to give the title compound (10 mg, 14% yield) as a whitesolid. ¹H NMR (CDCl₃, 300 MHz): δ 7.77 (d, J=2.1 Hz, 1H), 7.56 (s, 1H),7.04 (s, 1H), 7.01 (s, 1H), 6.26 (d, J=2.7 Hz, 1H), 4.88-4.84 (m, 1H),3.61 (s, 3H), 3.34-3.26 (m, 1H), 3.09 (q, J=7.5 Hz, 2H), 2.90-2.84 (m,1H), 2.21 (s, 3H), 1.87-1.82 (m, 1H), 1.72-1.63 (m, 1H), 1.56-1.43 (m,2H), 1.38 (t, J=7.2 Hz, 3H), 0.98 (t, J=7.5 Hz, 3H). LCMS: 391 (M+1)⁺.

Example 496:N-[2-cyclopropyl-7-(1,5-dimethyl-6-oxopyridin-3-yl)-2,3-dihydro-1-benzofuran-5-yl]ethanesulfonamide

To a mixture of the title compound from Example 495, Step 4 (30 mg, 0.08mmol) in Et₃SiH (1 mL) in a sealed tube was added TFA (0.2 mL) at 0° C.This was warmed to room temp and stirred overnight, then diluted withDCM (30 mL) and washed with 1N NaOH, H₂O, and brine. The organic phasewas dried over Na₂SO₄, filtered, and conc under reduced press. Theresidue was recrystallized from EtOAc to give the title compound (3 mg,10% yield) as a white solid. ¹H NMR (CDCl₃, 300 MHz): δ 7.77 (s, 1H),7.57 (s, 1H), 7.04 (d, J=3.0 Hz, 2H), 6.44 (s, 1H), 4.37-4.29 (m, 1H),3.63 (s, 3H), 3.37-3.29 (m, 1H), 3.13-3.03 (m, 3H), 2.22 (s, 3H), 1.40(t, J=7.5 Hz, 3H), 1.26-1.14 (m, 1H), 0.71-0.33 (m, 4H). LCMS: 389(M+1)⁺.

Example 497:4-[3-(methoxymethyl)-7-methylsulfonyl-2,3-dihydro-1,4-benzodioxin-5-yl]-2-methylisoquinolin-1-oneStep 1: (6-bromo-2,3-dihydro-1,4-benzodioxin-2-yl)methanol and(6-bromo-2,3-dihydro-1,4-benzodioxin-3-yl)methanol

To a mixture of NaOH (1.6 g, 39.7 mmol) in THF (120 mL) and H₂O (40 mL)was added 4-bromobenzene-1,2-diol (5 g, 26.5 mmol). Oxiran-2-ylmethanol(7.35 g, 79.5 mmol) was added portion-wise at room temp under N₂. Therxn was stirred at 100° C. for 4 hr; then cooled to room temp; andextracted with EtOAc (50 mL×2). The organic layers were washed withbrine (40 mL×2), dried over anhydrous Na₂SO₄, filtered, and conc underreduced press. The residue was purified by CC (PE:EA 5:1) to give thetitle compounds (4.7 g, 73%). LCMS: 166 (M−80)⁺.

Step 2: (6-methylsulfonyl-2,3-dihydro-1,4-benzodioxin-2-yl)methanol and(6-methylsulfonyl-2,3-dihydro-1,4-benzodioxin-3-yl)methanol

The mixture from Step 1 (1 g, 4.08 mmol) was submitted to theexperimental conditions described in Example 486, Step 1, to give amixture of the title compounds (650 mg, 65%). LCMS: 245.1 (M+1)⁺.

Step 3: 2-(methoxymethyl)-6-methylsulfonyl-2,3-dihydro-1,4-benzodioxineand 3-(methoxymethyl)-6-methylsulfonyl-2,3-dihydro-1,4-benzodioxine

To a soln of the mixture from Step 2 (2.5 g, 10.23 mmol) in THF (30 mL)was added NaH (614 mg, 15.35 mmol) at 0° C. The rxn was stirred at 0° C.for 1 hr. CH₃I (1.45 g, 10.23 mmol) was added to the rxn mixture whilekeeping the internal temp ˜0° C. The rxn mixture was stirred at roomtemp for another 3 hr, then quenched with ice and extracted with EtOAc(30 mL×3). The combined organic phases were washed with satd brine (20mL×2), dried over anhydrous Na₂SO₄, filtered and conc under reducedpress. The residue was purified by CC (PE:EA=3:1) to give a mixture ofthe title compounds (1.5 g, 57%) as an oil. The mixture was furtherseparated into its four individual components by chiral phase SFC togive the two enantiomers of2-(methoxymethyl)-6-methyl-sulfonyl-2,3-dihydro-1,4-benzodioxine (200mgs each) and the two enantiomers of3-(methoxy-methyl)-6-methylsulfonyl-2,3-dihydro-1,4-benzodioxine (200and 120 mgs, respectively). Their absolute stereochemistry was notassigned.2-(methoxymethyl)-6-methylsulfonyl-2,3-dihydro-1,4-benzodioxine ¹H NMR(CDCl₃, 400 MHz): δ7.44 (d, J=1.6 Hz, 1H), 7.41 (dd, J₁=8.8 Hz, J₂=2.0Hz, 1H), 7.03 (d, J=8.0 Hz, 1H), 4.42-4.31 (m, 2H), 4.10 (dd, J₁=11.6Hz, J₂=7.6 Hz, 1H), 3.71-3.58 (m, 2H), 3.42 (s, 3H), 3.01 (s, 3H). LCMS:259 (M+1)⁺.3-(methoxymethyl)-6-methylsulfonyl-2,3-dihydro-1,4-benzodioxine ¹H NMR(CDCl₃, 400 MHz): δ 7.47 (d, J=2.0 Hz, 1H), 7.41 (dd, J₁=8.8 Hz, J₂=2.0Hz, 1H), 7.00 (d, J=8.4 Hz, 1H), 4.40-4.30 (m, 2H), 4.18-4.10 (dd,J₁=11.2 Hz, J₂=7.2 Hz, 1H), 3.70-3.58 (m, 2H), 3.42 (s, 3H), 3.00 (s,3H). LCMS: 259 (M+1)⁺.

Step 4:5-bromo-3-(methoxymethyl)-7-methylsulfonyl-2,3-dihydro-1,4-benzodioxine

The title compound (single enantiomer, absolute stereochemistry notassigned) was prepared in a manner similar to Example 486, Step 2, bysubstituting2-(methoxymethyl)-6-methylsulfonyl-2,3-dihydro-1,4-benzodioxine for2-methyl-5-methylsulfonyl-2,3-dihydro-1-benzofuran. ¹H NMR (CDCl₃, 400MHz) δ 7.70 (d, J=2.0 Hz, 1H), 7.46 (d, J=2.0 Hz, 1H), 4.53 (dd, J₁=2.2Hz, J₂=11.4 Hz, 1H), 4.39-4.34 (m, 1H), 4.26-4.21 (m, 1H), 3.73-3.63 (m,2H), 3.45 (s, 3H), 3.03 (s, 3H).

Step 5:4-[3-(methoxymethyl)-7-methylsulfonyl-2,3-dihydro-1,4-benzodioxin-5-yl]-2-methylisoquinolin-1-one

A mixture of the title compound from Step 4 (20 mg, 0.06 mmol),2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1-one(20 mg, 0.07 mmol), Na₂CO₃ (19 mg, 0.18 mmol), Pd(dppf)Cl₂ (7 mg, 0.01mmol) in dioxane (2 mL) and H₂O (0.2 mL) was stirred at 80° C. for 12 hrunder N₂. The rxn mixture was poured over H₂O (10 mL) and extracted withEtOAc (3×10 mL). The combined organic phases were washed with brine (10mL), dried over anhydrous Na₂SO₄, filtered, and concentrated underreduced pressure to give a residue; then purified by CC followed byprep-HPLC to afford the title compound (12 mg, 24%). Absolutestereochemistry not assigned. ¹H NMR (DMSO-d6, 400 MHz) δ 8.30 (d, J=8.0Hz, 1H), 7.68-7.63 (m, 1H), 7.55-7.52 (m, 3H), 7.42 (s, 1H), 7.28 (d,J=8.4 Hz, 1H), 4.43-4.35 (m, 2H), 4.21-4.12 (m, 1H), 3.56 (s, 3H),3.44-3.41 (m, 2H), 3.23 (s, 3H), 3.09 (s, 3H). LCMS: 416.0 (M+H)⁺.

Example 498:5-[3-(methoxymethyl)-7-methylsulfonyl-2,3-dihydro-1,4-benzodioxin-5-yl]-1,3-dimethylpyridin-2-one

The title compound (single enantiomer, absolute stereochemistry notassigned) was prepared in a manner similar to Example 497, bysubstituting1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-onefor 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1-one in Step 5. ¹H NMR (CDCl₃, 400 MHz): δ 7.53 (s, 1H),7.49 (s, 1H), 7.43 (m, 2H), 4.45-4.37 (m, 2H), 4.18-4.17 (m, 1H),3.68-3.62 (m, 5H), 3.44 (s, 3H), 3.07 (s, 3H), 2.21 (s, 3H). LCMS: 380(M+H)⁺.

Example 499:4-[3-(methoxymethyl)-7-methylsulfonyl-2,3-dihydro-1,4-benzodioxin-5-yl]-2-methylisoquinolin-1-one

The title compound (single enantiomer, absolute stereochemistry notassigned) was prepared in a manner similar to Example 497, bysubstituting the compound used in Step 4 for its enantiomer. ¹H NMR(DMSO-d6, 400 MHz): δ 8.30 (d, J=8.0 Hz, 1H), 7.68 (t, J=8.0 Hz, 1H),7.55-7.51 (m, 3H), 7.42 (s, 1H), 7.28 (d, J=8.0 Hz, 1H), 4.42-4.35 (m,2H), 4.21-4.14 (m, 1H), 3.56 (s, 3H), 3.44-3.39 (m, 2H), 3.24 (s, 3H),3.09 (s, 3H). LCMS: 416.0 (M+H)⁺.

Example 500:5-[3-(methoxymethyl)-7-methylsulfonyl-2,3-dihydro-1,4-benzodioxin-5-yl]-1,3-dimethylpyridin-2-one

The title compound (single enantiomer, absolute stereochemistry notassigned) was prepared in a manner similar to Example 498, but using theother enantiomer of5-bromo-3-(methoxymethyl)-7-methylsulfonyl-2,3-dihydro-1,4-benzodioxine.¹H NMR (CDCl₃, 400 MHz) δ 7.59 (s, 1H), 7.58 (s, 1H), 7.44 (m, 2H),4.41-4.37 (m, 2H), 4.20-4.18 (m, 1H), 3.71-3.63 (m, 5H), 3.44 (s, 3H),3.07 (s, 3H), 2.24 (s, 3H). LCMS: 380.0 (M+H)⁺.

Example 501:4-[2-(methoxymethyl)-7-methylsulfonyl-2,3-dihydro-1,4-benzodioxin-5-yl]-2-methylisoquinolin-1-oneStep 1:5-bromo-2-(methoxymethyl)-7-methylsulfonyl-2,3-dihydro-1,4-benzodioxine

The title compound (single enantiomer, absolute stereochemistry notassigned) was prepared in a manner similar to Example 497, Step 4, bysubstituting2-(methoxymethyl)-6-methylsulfonyl-2,3-dihydro-1,4-benzodioxine for3-(methoxymethyl)-6-methylsulfonyl-2,3-dihydro-1,4-benzodioxine. LCMS:359 (M+23)⁺.

Step 2:4-[2-(methoxymethyl)-7-methylsulfonyl-2,3-dihydro-1,4-benzodioxin-5-yl]-2-methylisoquinolin-1-one

The title compound (single enantiomer, absolute stereochemistry notassigned) was prepared in a manner similar to Example 497, Step 5, bysubstituting5-bromo-2-(methoxymethyl)-7-methylsulfonyl-2,3-dihydro-1,4-benzodioxinefor5-bromo-3-(methoxymethyl)-7-methylsulfonyl-2,3-dihydro-1,4-benzodioxine.¹H NMR (DMSO-d₆, 400 MHz): δ 8.31 (d, J=8.0 Hz, 1H), 7.66-7.63 (m, 1H),7.56-7.51 (m, 3H), 7.40 (s, 1H), 7.30-7.16 (m, 1H), 4.53-4.44 (m, 1H),4.36-4.28 (m, 1H), 4.12-4.01 (m, 1H), 3.61-3.56 (m, 5H), 3.34 (s, 3H),3.24 (s, 3H). LCMS: 416.0 (M+H)⁺.

Example 502:5-[2-(methoxymethyl)-7-methylsulfonyl-2,3-dihydro-1,4-benzodioxin-5-yl]-1,3-dimethylpyridin-2-one

The title compound (single enantiomer, absolute stereochemistry notassigned) was prepared in a manner similar to Example 501, bysubstituting1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-onefor2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1-one.¹H NMR (CDCl₃, 400 MHz) δ 7.48 (m, 3H), 7.41 (d, J=2.4 Hz, 1H),4.47-4.34 (m, 2H), 4.19-4.16 (m, 1H), 3.71-3.65 (m, 5H), 3.45 (s, 3H),3.05 (s, 3H), 2.22 (s, 3H). LCMS: 380.0 (M+H)⁺.

Example 503:4-[2-(methoxymethyl)-7-methylsulfonyl-2,3-dihydro-1,4-benzodioxin-5-yl]-2-methylisoquinolin-1-one

The title compound (single enantiomer, absolute stereochemistry notassigned) was prepared in a manner similar to Example 501, bysubstituting the compound used in Step 1 for its enantiomer. ¹H NMR(CD₃OD, 400 MHz) δ8.41 (d, J=8.0 Hz, 1H), 7.70 (t, J=7.6 Hz, 1H),7.58-7.54 (m, 2H), 7.48 (s, 1H), 7.42 (s, 1H), 7.33-7.30 (m, 1H),4.52-4.41 (m, 2H), 4.20-4.12 (m, 1H), 3.67 (s, 3H), 3.47 (m, 2H),3.19-3.15 (m, 6H). LCMS: 416.0 (M+H)⁺.

Example 504:4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methyl-6,7-dihydro-5H-cyclopenta[c]pyridin-1-oneStep 1: ethyl 6,7-dihydro-5H-cyclopenta[c]pyridine-1-carboxylate

Ethyl 1,2,4-triazine-3-carboxylate (7 g, 45.8 mmol), cyclopentanone (4.9mL, 55.0 mmol), and pyrrolidine (4.6 mL, 55.0 mmol) in toluene (100 mL)were heated to reflux for 12 hr. The mixture was purified by column onsilica gel chromatography (PE/EtOAc=5:1) to give the title compound(2.02 g, 25%) as a brown oil. LCMS: 192 (M+1)⁺.

Step 2: 6,7-dihydro-5H-cyclopenta[c]pyridine-1-carboxylic acid

A 2N soln of LiOH (50 mL) in H₂O was slowly added to the title compoundof step 1 (10 g, 52.4 mmol) in MeOH (250 mL) at 0° C. The mixture waswarmed to room temp and stirred for 30 min. The MeOH was reduced undervacuum and the residual aq soln was washed with EtOAc. The organic phasewas re-extracted with H₂O. The combined aq extracts were acidified to pH2 with 1N HCl. The H₂O was removed and preparative HPLC gave the titlecompound (5.4 g, 63%) as a white solid. ¹H NMR (CD₃OD, 400 MHz): δ 8.45(d, J=5.6 Hz, 1H), 7.88 (d, J=5.6 Hz, 1H), 3.39 (t, J=8.0, 7.6 Hz, 2H),3.16 (d, t, J=8.0, 7.6 Hz, 2H), 2.16-2.20 (m, 2H).

Step 3: tert-butyl N-(6,7-dihydro-5H-cyclopenta[c]pyridin-1-yl)carbamate

The title compound of step 2 (1.0 g, 6.1 mmol), diphenylphosphoryl azide(2.64 mL 12.2 mmol), and triethylamine (1.64 mL, 12.2 mmol) in tBuOH (50mL), under N₂, were heated at 80° C. for 2 hr. Silica gel chromatography(PE:EtOAc 5:1) gave the title compound (570 mg, 40%) as a white solid.¹H NMR (CDCl₃, 300 MHz): δ 8.18 (d, J=4.8 Hz, 1H), 7.04 (d, J=4.8 Hz,1H), 2.90-2.97 (m, 4H), 2.06-2.12 (m, 2H), 1.49 (s, 9H). LCMS: 235(M+1)⁺.

Step 4: 6,7-dihydro-5H-cyclopenta[c]pyridin-1-amine hydrochloride

Anhydrous 1M HCl in DCM (20 mL) was added slowly to the title compoundof step 3 (570 mg, 2.43 mmol) in DCM (10 mL) at 0° C. After stirring atroom temp for 1.5 hr, evaporation of the volatile components gave thetitle compound (400 mg, 96%) as a white solid. ¹H NMR (CD₃OD, 300 MHz):δ 7.66 (d, J=6.6 Hz, 1H), 6.88 (d, J=6.6 Hz, 1H), 3.04 (t, J=7.8, 7.2Hz, 2H), 2.86 (t, J=7.8, 7.2 Hz, 2H), 2.17-2.27 (m, 2H). LCMS: 135(M+1)⁺.

Step 5: 2,5,6,7-tetrahydrocyclopenta[c]pyridin-1-one

The title compound of step 4 (400 mg, 2.33 mmol) was dissolved in H₂O(6.5 mL) and H₃PO₂ (2 mL, 50% w/w in H₂O, 18.64 mmol) was added. Themixture was cooled to 0° C. and a soln of NaNO₂ (180 mg 2.68 mmol) inH₂O (6.5 mL) was added dropwise. The mixture was stirred at 0° C. for 1hr and then at room temp overnight. The pH 7 was obtained by carefuladdition of NaHCO₃. Extractive work-up using EtOAc gave the titlecompound (300 mg, 95%) as a yellow solid. ¹H NMR (CDCl₃, 300 MHz): δ12.55 (s, 1H), 7.24 (d, J=6.3 Hz, 1H), 6.26 (d, J=6.3 Hz, 1H), 2.84-2.89(m, 4H), 2.04-2.11 (m, 2H). LCMS: 136 (M+1)⁺.

Step 6: 2-methyl-6,7-dihydro-5H-cyclopenta[c]pyridin-1-one

The title compound of step 5 (260 mg, 1.93 mmol) was dissolved in DMF (5mL) and cooled to 0° C. NaH (94 mg, 2.31 mmol) was added and the mixturewas stirred for 30 min. Methyl iodide (146 μL, 2.31 mmol) was added andthe mixture stirred at room temp for 2 hr. The volatile components wereremoved under vacuum and silica gel chromatography (PE:EtOAc 1:1) gavethe title compound (192.6 mg, 67%) as a brown oil. ¹H NMR (CD₃Cl, 300MHz): δ 7.13 (d, J=6.6 Hz, 1H), 6.13 (d, J=6.6 Hz, 1H), 3.53 (s, 3H),2.79-2.85 (m, 4H), 2.01-2.11 (m, 2H). LCMS: 150 (M+1)⁺.

Step 7: 4-bromo-2-methyl-6,7-dihydro-5H-cyclopenta[c]pyridin-1-one

The title compound of step 6 (140 mg, 1.04 mmol) was dissolved in ACN (5mL) and NBS (188 mg, 1.06 mmol) was added. After stirring at room tempfor 1.5 hr, purification by silica gel chromatography (PE:EtOAc 1:1)gave the title compound (196 mg, 89.5%) as a white solid. ¹H NMR (CD₃Cl,300 MHz): δ 7.33 (s, 1H), 3.53 (s, 3H), 2.85-2.97 (m, 4H), 2.05-2.13 (m,2H). LCMS: 228, 230 (M+1)⁺.

Step 8:4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methyl-6,7-dihydro-5H-cyclopenta[c]pyridin-1-one

To a soln of the title compound of step 7 (60 mg, 0.26 mmol), the titlecompound of Example 90, step 1 (111.2 mg, 0.32 mmol) and K₂CO₃ (107 mg,0.78 mmol) in dioxane (4 mL) and H₂O (1 mL) was added Pd(dppf)Cl₂ (6 mg)under N₂. The mixture was heated at 85° C. overnight. EA extractivework-up followed by prep-TLC (DCM:MeOH=25:1) gave the title compound (47mg, 48%) as a yellow solid. ¹H NMR (DMSO-d₆, 300 MHz): δ 7.83 (dd,J=8.7, 2.7 Hz, 1H), 7.66 (d, J=2.9 Hz, 1H), 7.58 (s, 1H), 7.25 (d, J=8.7Hz, 1H), 3.95 (d, J=6.9 Hz, 2H). 3.46 (s, 3H), 3.17 (s, 3H), 2.65-2.70(m, 4H), 1.91-1.97 (m, 2H), 1.13-1.18 (m, 1H), 0.50-0.54 (m, 2H),0.26-0.30 (m, 2H). LCMS: 374 (M+1)⁺.

Example 505:4-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-2-methyl-6,7-dihydro-5H-cyclopenta[c]pyridin-1-one

The title compound was prepared in a similar manner to Example 504, step8 except that2-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolanewas substituted for the title compound of Example 90, step 1. ¹H NMR(CD₃OD, 400 MHz): δ 7.91 (dd, J=8.4, 2.0 Hz, 1H), 7.73 (d, J=2.0 Hz,1H), 7.56 (s, 1H), 7.27 (d, J=8.4 Hz, 1H), 4.01 (d, J=6.8 Hz, 2H), 3.66(s, 3H), 3.23 (q, J=7.6 Hz, 2H), 2.88 (t, J=7.6 Hz, 2H), 2.82 (t, J=7.6Hz, 2H), 2.08-2.14 (m, 2H), 1.26 (t, J=7.6 Hz, 3H), 1.08-1.27 (m, 1H),0.60-0.65 (m, 2H), 0.33-0.37 (m, 2H). LCMS: 388 (M+1)⁺.

Example 506:N-[4-(2,4-difluorophenoxy)-3-(2-methyl-1-oxo-6,7-dihydro-5H-cyclopenta[c]pyridin-4-yl)phenyl]methanesulfonamide

The title compound was prepared in a similar manner to Example 504, step8, except thatN-[4-(2,4-difluorophenoxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanesulfonamidewas substituted for the title compound of Example 90, step 1. ¹H NMR(DMSO-d6, 400 MHz): δ 9.72 (s, 1H), 7.58 (s, 1H), 7.34-7.42 (m, 1H),7.24-7.10 (m, 2H), 7.00-7.08 (m, 2H), 6.91 (d, J=8.4 Hz, 1H), 3.43 (s,3H), 3.01 (s, 3H), 2.71 (t, J=7.2 Hz, 2H), 2.65 (t, J=7.2 Hz, 2H),1.88-1.96 (m, 2H). LCMS: 447 (M+1)⁺.

Example 507:N-[4-(2,4-difluorophenoxy)-3-(2-methyl-1-oxo-6,7-dihydro-5H-cyclopenta[c]pyridin-4-yl)phenyl]ethanesulfonamide

The title compound was prepared in a similar manner to Example 504, step8 except thatN-[4-(2,4-difluorophenoxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethane-sulfonamidewas substituted for the title compound of Example 90, step 1. ¹H NMR(CD₃Cl, 400 MHz): δ 7.30 (s, 1H), 7.19 (d, J=3.2 Hz, 1H), 7.14 (dd,J=8.8, 3.2 Hz, 1H), 6.89-6.96 (m, 2H), 6.79-6.85 (m, 1H); 6.77 (d, J=8.8Hz, 1H), 6.60 (s, 1H), 3.65 (s, 3H), 3.15 (q, J=7.6 Hz, 2H), 2.96 (t,J=7.6 Hz, 2H), 2.82 (t, J=7.6 Hz, 2H), 2.02-2.06 (m, 2H), 1.41 (t, J=7.6Hz, 3H). LCMS: 461 (M+1)⁺.

Examples 508-511 as described in Table 22 were prepared in three steps.Using conditions similar to those described in WO 2005/40151(Preparation 6), 5-bromo-3-methylpyridin-2-ol was N-alkylated withisopropyl bromide to give 5-bromo-3-methyl-1-propan-2-ylpyridin-2-onewhich was then reacted with4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolaneusing conditions similar to those described in Example 248, step 2 togive the pinacol ester,3-methyl-1-propan-2-yl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one.This pinacol ester was then substituted for the pinacol ester of theexample shown under Synthetic Method in Table 22 and reacted in the sameway as the example to obtain the title compounds.

TABLE 22

Ex. MS Synthetic No. R¹ Name (M + H) Method 508

5-(5-butyl-2-methylsulfonylpyrimidin-4-yl)-3-methyl-1-propan-2-ylpyridin-2-one 364 Example 305 509

N-[5-(2,4-difluorophenoxy)-4-(5-methyl- 6-oxo-1-propan-2-ylpyridin-3-yl)pyrimidin-2-yl]ethanesulfonamide 465 Example 169 510

5-[5-(2,4-difluorophenoxy)-2- methyl]sulfonylpyrimidin-4-yl]-3-methyl-1-propan-2-ylpyridin-2-one 436 Example 149, step 4 511

N-[5-butyl-4-(5-methyl-6-oxo-1-propan- 2-ylpyridin-3-yl)pyrimidin-2-yl]ethanesulfonamide 393 Example 310

Examples 512-514 as described in Table 23 were prepared in three steps.Using conditions similar to those described by Malhotra et. al., 15(24)Organic Letters 3698 (2013), (supporting information, compounds 4c and3a), 3,5-dibromo-1-methylpyridin-2-one was alkylated at the 3-positionusing isopropylmagnesium bromide to give5-bromo-1-methyl-3-propan-2-yl-pyridin-2-one which was then reacted with4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolaneusing conditions similar to those described in Example 248, step 2 togive the pinacol ester,1-methyl-3-propan-2-yl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one.This pinacol ester was then substituted for the pinacol ester of theexample shown under Synthetic Method in Table 23 and reacted in the sameway as the example to obtain the title compounds.

TABLE 23

Ex. MS Synthetic No. R¹ Name (M + H) Method 512

N-[5-butyl-4-(1-methyl-6-oxo-5- propan-2-ylpyridin-3-yl)pyrimidin-2-yl]ethanesulfonamide 393 Example 310 513

5-(5-butyl-2- methylsulfonylpyrimidin-4-yl)-1-methyl-3-propan-2-ylpyridin-2-one 364 Example 305 514

N-[5-(2,4-difluorophenoxy)-4-(1- methyl-6-oxo-5-propan-2-ylpyridin-3-yl)pyrimidin-2-yl]ethanesulfonamide 465 Example 169

II. Biological Evaluation Example 1: In Vitro Enzyme Inhibition Assay

Determination of the IC₅₀ for the heterocyclic derivative BRD4inhibitors disclosed herein was performed as follows. His-tagged BRD4was cloned, expressed and purified to homogeneity. Filipakopoulos etal., Nature 468:1067 (2010). BRD4 binding and inhibition was assessed bymonitoring the interaction of biotinylated H4-tetraacetyl peptide(AnaSpec, H4K5/8/12/16(Ac), biotin-labeled) with the target using theAlphaScreen technology (Life Technologies). In a 384-well ProxiPlateBRD4(BD1) (2 nM final) was combined with peptide (15 nM final) in 50 mMHEPES (pH 7.3), 10 mM NaCl, 0.25 mM TCEP, 0.1% (w/v) BSA, and 0.005%(w/v) Brij-35 either in the presence of DMSO (final 0.4% DMSO) orcompound dilution series in DMSO. After 20 min incubation at room temp,Alpha streptavidin donor beads and Nickel Chelate acceptor beads wereadded to a final concentration of 5 μg/mL. After 2 hr of equilibration,plates were read on an Envision instrument and the IC₅₀ was calculatedusing a four parameter non-linear curve fit. Chemistry Example 1(2-methyl-4-phenylisoquinolin-1-one) had an IC₅₀ of 2.782 μM in thisassay format.

The ability of the compounds disclosed herein to inhibit BRD4 activitywas quantified and the respective IC₅₀ value was determined. The IC₅₀values of various compounds disclosed herein is provided in Table 24.

Example 2: In Vitro Cell-based Assay

A colorimetric cellular proliferation assay (Cell-MTS assay) wasperformed to assess the ability of the heterocyclic derivative BRD4inhibitors disclosed herein to effect the proliferation of establishedcancer cell lines.

Assay Principle

The Cell-MTS assay is a 7-day plate-based colorimetric assay whichquantifies the amount of newly generated NADH in the presence or absenceof test compound. The NADH level is used for the quantification ofcancer cell proliferation.

Assay Method

Established cancer cell lines with a variety of driving mutations wereobtained from American Type Culture Collection (ATCC) and routinelypassaged according to ATCC protocols. For routine assay, these cellswere seeded at densities which enabled ˜90% confluence after 7 days ofculture. Raji, human Burkitts lymphoma cells, (cMYC) were seeded at15,000 cells per 96-well. HL-60, human proleukemia cells, (NRAS, p16,p53, c-Myc amplified) were seeded at 5,000 cells per 96-well. NCI-H460,human non-small cell lung cancer cells, (KRAS, PIK3CA, STLK11, p16) wereseeded at 3,000 cells per 96-well. 24 hr after plating, cells receivedan 11-point dilution of test compound with final concentration rangesfrom 100 μM to 2.0 nM. Cells were incubated in the presence of compoundfor 168 hr at 37° C., and 5% CO₂. At the end of this incubation period,80 μL of media is removed and 20 μL of CellTiter 96® AQueousNon-Radioactive Cell Proliferation Assay soln (Promega) was added. Thecells were incubated until the OD₄₉₀ was >0.6. IC₅₀ values werecalculated using the IDBS XLfit software package and include backgroundsubtracted OD₄₉₀ values and normalization to DMSO controls. Cellularproliferation IC₅₀ values were uploaded and archived using the ChemBiography Platform.

Table 24 provides the results of the in vitro enzyme inhibition assayexperiments and the in vitro cell-based assay experiments performed withthe compounds disclosed herein.

TABLE 24 Chem. Synth. BRD4 Raji HL-60 H460 Example Name IC₅₀ (μM) IC₅₀(μM) IC₅₀ (μM) IC₅₀ (μM) 1 4-(3-methoxyphenyl)-2- Bmethylisoquinolin-1-one 2 2-methyl-4-phenylisoquinolin-1- B one 34-(2-fluorophenyl)-2- C methylisoquinolin-1-one 4 4-(2-methoxyphenyl)-2-C methylisoquinolin-1-one 5 4-(3-aminophenyl)-2- Bmethylisoquinolin-1-one 6 N-cyclopropyl-3-(2-methyl-1- Boxoisoquinolin-4- yl)benzenesulfonamide 7 2-methyl-4-(3-pyrrolidin-1- BA B ylsulfonylphenyl)isoquinolin-1-one 8N-[[3-(2-methyl-1-oxoisoquinolin-4- Byl)phenyl]methyl]methanesulfonamide 9 N-[3-(2-methyl-1-oxoisoquinolin-4-A A A C yl)phenyl]methanesulfonamide 10 N-ethyl-3-(2-methyl-1- Boxoisoquinolin-4- yl)benzenesulfonamide 11 4-(3-ethylsulfonylphenyl)-2-B A B methylisoquinolin-1-one 12 4-[3-(dimethylsulfamoylamino)phenyl]- AA A 2-methyl-1-oxoisoquinoline 13 N-[3-(2-methyl-1-oxoisoquinolin-4- A AA yl)phenyl]ethanesulfonamide 14 2-methyl-4-(3-morpholin-4- Byl-sulfonylphenyl)isoquinolin-1-one 15 N-benzyl-2-methoxy-5-(2-methyl- BA B 1-oxoisoquinolin-4- yl)benzenesulfonamide 162-methoxy-5-(2-methyl-1- B oxoisoquinolin-4- yl)benzenesulfonamide 17N-[2-methyl-5-(2-methyl-1- A B A oxoisoquinolin-4- yl)phenyl]methanesulfonamide 18 N-benzyl-2-methoxy-5-(2-methyl- B B B1-oxoisoquinolin-4-yl)benzamide 19 4-(3,4-dihydro-2H-1,4-benzoxazin- B6-yl)-2-methylisoquinolin-1-one 20 2-methyl-4-(2-oxo-1,3- C A Adihydroindol-6-yl)isoquinolin-1-one 21 3-(2-methyl-1-oxoisoquinolin-4- BB B yl)benzenesulfonamide 22 N-(2-hydroxyethyl)-3-(2-methyl-1- B B Boxoisoquinolin-4- yl)benzenesulfonamide 23 4-(5-amino-2-fluorophenyl)-2-B methylisoquinolin-1-one 24 4-(5-amino-2,4-difluorophenyl)-2- Bmethylisoquinolin-1-one 25 4-(3-amino-5-fluorophenyl)-2- Bmethylisoquinolin-1-one 26 4-(3-amino-4-fluorophenyl)-2- Bmethylisoquinolin-1-one 27 N-benzyl-3-(2-methyl-1- B oxoisoquinolin-4-yl)benzenesulfonamide 28 N-[3-(2-methyl-1-oxoisoquinolin-4- A B Byl)phenyl]propane-1-sulfonamide 29 N-[3-(2-methyl-1-oxoisoquinolin-4- AB B yl)phenyl]butane-1-sulfonamide 30 N-[2-methoxy-5-(2-methyl-1- A B Aoxoisoquinolin-4- yl)phenyl]methanesulfonamide 31 tert-butylN-methyl-N-[3-(2- B B B methyl-1-oxoisoquinolin-4- yl)phenyl]carbamate32 2-methyl-4-[3- B (methylamino)phenyl]isoquinolin- 1-one 33N-methyl-N-[3-(2-methyl-1- A B B oxoisoquinolin-4-yl)phenyl]methanesulfonamide 34 N-[4-fluoro-3-(2-methyl-1- A A Aoxoisoquinolin-4- yl)phenyl]methanesulfonamide 35N-[2,4-difluoro-5-(2-methyl-1- B B B oxoisoquinolin-4-yl)phenyl]methanesulfonamide 36 N-[3-fluoro-5-(2-methyl-1- B B Boxoisoquinolin-4- yl)phenyl]methanesulfonamide 37N-[2-fluoro-5-(2-methyl-1- A B B oxoisoquinolin-4-yl)phenyl]methanesulfonamide 38 N-[4-chloro-3-(2-methyl-1- A B Aoxoisoquinolin-4- yl)phenyl]methanesulfonamide 39N-[4-methyl-3-(2-methyl-1- A B A oxoisoquinolin-4-yl)phenyl]methanesulfonamide 40 N-[3-(2-methyl-1-oxoisoquinolin-4-yl)- BB B 5-(trifluoromethyl)phenyl]methane- sulfonamide 41N-[4-fluoro-3-[2-methyl-6-(1- A A A methyl-pyrazol-4-yl)-1-oxoisoquinolin-4- yl]phenyl]methanesulfonamide 42 N-[3-[2-methyl-6-(1- AA A methylpyrazol-4-yl)-1- oxoisoquinolin-4-yl]phenyl]methanesulfonamide 43 N-[2,4-difluoro-5-[2-methyl-6-(1- A A Amethylpyrazol-4-yl)-1- oxoisoquinolin-4- yl]phenyl]methanesulfonamide 444-(3-ethylsulfonylphenyl)-2- A B A C methyl-6-(1-methylpyrazol-4-yl)isoquinolin-1-one 45 N-[4-chloro-3-[2-methyl-6-(1- A A A Bmethylpyrazol-4-yl)-1- oxoisoquinolin-4- yl]phenyl]ethanesulfonamide 464-[2-(cyclopropylmethoxy)-5- A A A C methylsulfonylphenyl]-2-methyl-6-(1-methylpyrazol-4-yl)isoquinolin- 1-one 47 N-[3-(6-fluoro-2-methyl-1- AA A oxoisoquinolin-4- yl)phenyl]methanesulfonamide 483-(6-fluoro-2-methyl-1- B B B oxoisoquinolin-4- yl)benzenesulfonamide 49N-ethyl-3-(6-fluoro-2-methyl-1- B B B oxoisoquinolin-4-yl)benzenesulfonamide 50 N-[4-chloro-3-(6-fluoro-2-methyl- A B A B1-oxoisoquinolin-4- yl)phenyl]ethanesulfonamide 51N-[3-(2-methyl-1-oxo-2,7- B C B naphthyridin-4-yl)phenyl]methanesulfonamide 52 N-[3-(2-methyl-1-oxo-2,7- B B Bnaphthyridin-4- yl)phenyl]ethanesulfonamide 53N-ethyl-3-(2-methyl-1-oxo-2,7- B C C naphthyridin-4-yl)benzenesulfonamide 54 N-benzyl-2-methoxy-5-(2-methyl- C C B C1-oxo-2,7-naphthyridin-4- yl)benzenesulfonamide 553-(2-methyl-1-oxo-2,7- C naphthyridin-4- yl)benzenesulfonamide 562-methoxy-5-(2-methyl-1-oxo-2,7- C naphthyridin-4- yl)benzenesulfonamide57 N-[4-(2,4-difluorophenoxy)-3-(2- A A A Cmethyl-1-oxo-2,7-naphthyridin-4- yl)phenyl]ethanesulfonamide 58N-[3-(7-fluoro-2-methyl-1- A B A oxoisoquinolin-4- yl)phenyl]methanesulfonamide 59 N-ethyl-3-(7-fluoro-2-methyl-1- B B Boxoisoquinolin-4- yl)benzenesulfonamide 60N-benzyl-5-(7-fluoro-2-methyl-1- B A B C oxoisoquinolin-4-yl)-2-methoxybenzenesulfonamide 61 3-(7-fluoro-2-methyl-1- A B Boxoisoquinolin-4- yl)benzenesulfonamide 62 N-[3-(7-fluoro-2-methyl-1- AB A oxoisoquinolin-4- yl)phenyl] ethanesulfonamide 634-(3-ethylsulfonylphenyl)-7-fluoro- B B B C 2-methylisoquinolin-1-one 645-(7-fluoro-2-methyl-1- B oxoisoquinolin-4-yl)-2-methoxybenzenesulfonamide 65 2-methyl-4-(1-methylpyrazol-4- Byl)isoquinolin-1-one 66 4-(furan-2-yl)-2-methylisoquinolin- C 1-one 672-methyl-4-(1,3-oxazol-2- C yl)isoquinolin-1-one 682-methyl-4-(1H-pyrazol-5- C yl)isoquinolin-1-one 692-methyl-4-(1-methylimidazol-2- C yl)isoquinolin-1-one 702-methyl-4-pyridin-2-ylisoquinolin- C 1-one 71 2-methyl-4-pyrimidin-2- Cylisoquinolin-1-one 72 N-[3-[2-methyl-6-(6-methylpyridin- A A A B3-yl)-1-oxoisoquinolin-4- yl]phenyl]ethanesulfonamide 73N-[3-(2-methyl-1-oxo-6- B phenylisoquinolin-4-yl)phenyl]ethanesulfonamide 74 N-[3-(2-methyl-1-oxo-6- B B B Cphenylisoquinolin-4- yl)phenyl]methanesulfonamide 75N-[3-(2,6-dimethyl-1- A A A C oxoisoquinolin-4-yl)phenyl]ethanesulfonamide 76 N-[3-(6-ethyl-2-methyl-1- Aoxoisoquinolin-4- yl)phenyl]ethanesulfonamide 77N-[3-(6-ethyl-2-methyl-1- A A A C oxoisoquinolin-4-yl)phenyl]methanesulfonamide 78 N-[3-(2,6-dimethyl-1- A A A Coxoisoquinolin-4- yl)phenyl]methanesulfonamide 79 4-(5-ethylsulfonyl-2-A A A C methoxyphenyl)-2-methyl-6-(1- methylpyrazol-4-yl) isoquinolin-1-one 80 4-(5-ethylsulfonyl-2- A hydroxyphenyl)-2-methyl-6-(1-methylpyrazol-4-yl)isoquinolin-1- one 81 4-(2-ethoxy-5- A A A Aethylsulfonylphenyl)-2-methyl-6- (1-methylpyrazol-4-yl) isoquinolin-1-one 82 4-[2-(cyclopropylmethoxy)-5- A A A Bethylsulfonylphenyl]-2-methyl-6- (1-methylpyrazol-4-yl)isoquinolin-1-one 83 4-(5-ethylsulfonyl-2- A A A A propoxyphenyl)-2-methyl-6-(1-methylpyrazol-4-yl) isoquinolin-1-one 84 4-[5-ethylsulfonyl-2-(2- A B AB hydroxyethoxy)phenyl]-2-methyl- 6-(1-methylpyrazol-4-yl)isoquinolin-1-one 85 4-[2-(2-aminoethoxy)-5- A C B Cethylsulfonylphenyl]-2-methyl-6- (1-methylpyrazol-4-yl)isoquinolin-1-one 86 N-[2-fluoro-4-methoxy-5-[2- A A A Bmethyl-6-(1-methylpyrazol-4-yl)-1- oxoisoquinolin-4-yl]phenyl]ethanesulfonamide 87 N-[3-(2-methyl-1-oxo-6-pyridin-2- B B A Cylisoquinolin-4- yl)phenyl] ethanesulfonamide 884-[4-fluoro-2-methoxy-5- A A A C (methylsulfonylmethyl)phenyl]-2-methyl-6-(1-methylpyrazol-4- yl) isoquinolin-1-one 894-[2-(cyclopropylmethoxy)-5- A A A C methylsulfonylphenyl]-2-methylisoquinolin-1-one 90 4-[2-(cyclopropylmethoxy)-5- A A Amethylsulfonylphenyl]-6-fluoro-2- methylisoquinolin-1-one 914-[2-(cyclopropylmethoxy)-5- A A A C methylsulfonylphenyl]-7-fluoro-2-methylisoquinolin-1-one 92 4-[2-(2,4-difluorophenoxy)-5- A A A Cmethylsulfonylphenyl]-2- methylisoquinolin-1-one 93N-[4-(2,4-difluorophenoxy)-3-(2- A A A C methyl-1-oxoisoquinolin-4-yl)phenyl] ethanesulfonamide 94 N-[3-(1-methyl-6-oxopyridin-3- B A Cyl)phenyl]methanesulfonamide 95 N-[3-(1,4-dimethyl-6-oxopyridin-3- Byl)phenyl]methanesulfonamide 96 N-[3-(1,5-dimethyl-6-oxopyridin-3- Byl)phenyl]methanesulfonamide 97 N-[3-(1,4,5-trimethyl-6-oxopyridin- B3-yl)phenyl]methanesulfonamide 98 5-[2-(cyclopropylmethoxy)-5- B B B Cmethylsulfonylphenyl]-1- methylpyridin-2-one 99N-[4-(2,4-difluorophenoxy)-3-(1- A A A C methyl-6-oxopyridin-3-yl)phenyl]ethanesulfonamide 100 N-[4-(2,4-difluorophenoxy)-3-(1- A A A Cmethyl-6-oxopyridin-3- yl)phenyl] methanesulfonamide 101N-[4-(2,4-difluorophenoxy)-3-(1,4- A A A C dimethyl-6-oxopyridin-3-yl)phenyl]methanesulfonamide 102 N-[4-(2,4-difluorophenoxy)-3-(1,5- A AA C dimethyl-6-oxopyridin-3- yl)phenyl]methanesulfonamide 103N-[4-(2,4-difluorophenoxy)-3- A B A C (1,4,5-trimethyl-6-oxopyridin-3-yl)phenyl]methanesulfonamide 104 3-amino-1-methyl-5-(3- Cmethylsulfonylphenyl)pyrazin-2-one 1053-amino-5-(3-ethylsulfonylphenyl)- C 1-methylpyrazin-2-one 106N-[5-(6-amino-4-methyl-5- C oxopyrazin-2-yl)-2- methoxyphenyl]methanesulfonamide 107 3-amino-1-methyl-5-(3- Cmethylsulfonylphenyl)pyridin-2-one 1083-amino-5-(3-ethylsulfonylphenyl)- C 1-methylpyridin-2-one 109N-[5-(5-amino-1-methyl-6- B C C C oxopyridin-3-yl)-2- methoxyphenyl]methanesulfonamide 110 N-[2-methoxy-5-[1-methyl-5- A C B C(methylamino)-6-oxopyridin-3- yl]phenyl]methanesulfonamide 111N-[5-[5-(ethylamino)-1-methyl-6- B oxopyridin-3-yl]-2- methoxyphenyl]methanesulfonamide 112 N-[5-[5-(cyclopropylmethylamino)- B1-methyl-6-oxopyridin-3-yl]-2- methoxyphenyl]methanesulfonamide 113N-[5-[5-(dimethylamino)-1-methyl- A B A B 6-oxopyridin-3-yl]-2-methoxyphenyl] methanesulfonamide 114 N-[5-[5-(diethylamino)-1-methyl-6-B oxopyridin-3-yl]-2- methoxyphenyl]methanesulfonamide 115N-[3-(5-amino-1-methyl-6- A A A C oxopyridin-3-yl)-4-(2,4-difluorophenoxy)phenyl] ethane- sulfonamide 116 3-amino-5-[2- A C B C(cyclopropylmethoxy)-5- methylsulfonylphenyl]-1- methylpyridin-2-one 1174-ethoxy-3-(1-methyl-6- A B B C oxopyridin-3- yl) benzenesulfonamide 1184-(2,4-difluorophenoxy)-3-(1- A A A C methyl-6-oxopyridin-3-yl)benzenesulfonamide 119 5-[2-(cyclopropylmethoxy)-5- B B B Cmethylsulfonylphenyl]-3-fluoro-1- methylpyridin-2-one 1205-[2-(2,4-difluorophenoxy)-5- B C B C methylsulfonylphenyl]-3-fluoro-1-methylpyridin-2-one 121 5-[2-(2,4-difluorophenoxy)-5- A B A Cethylsulfonylphenyl]-3-fluoro-1- methylpyridin-2-one 122N-[4-(2,4-difluorophenoxy)-3-(5- A A A C fluoro-1-methyl-6-oxopyridin-3-yl)phenyl]ethanesulfonamide 123 N-[3-(2-methyl-1-oxo-2,6- B B B Cnaphthyridin-4- yl)phenyl]ethanesulfonamide 124N-ethyl-3-(2-methyl-1-oxo-2,6- B naphthyridin-4-yl)benzenesulfonamide125 N-[3-(2-methyl-1-oxo-2,6- B naphthyridin-4-yl)phenyl]methanesulfonamide 126 4-(3-ethylsulfonylphenyl)-2- Cmethyl-2,6-naphthyridin-1-one 127 N-[4-(2,4-difluorophenoxy)-3-(2- A A AC methyl-1-oxo-2,6-naphthyridin-4- yl)phenyl]ethanesulfonamide 1284-[2-(cyclopropylmethoxy)-5- A A A C methylsulfonylphenyl]-2-methyl-6-(4-methylpyrazol-1-yl)isoquinolin- 1-one 129N-[4-(2,4-difluorophenoxy)-3-(7- A A A C methyl-8-oxoimidazo[1,5-a]pyrazin-5- yl) phenyl]ethanesulfonamide 1305-[2-(cyclopropylmethoxy)-5- A B A C methylsulfonylphenyl]-7-methylimidazo[1,5-a]pyrazin-8-one 131 7-methyl-5-(3- Cmethylsulfonylphenyl) imidazo [1,5- a]pyrazin-8-one 132N-[2-methoxy-5-(7-methyl-8- B C B B oxoimidazo[1,5-a]pyrazin-5-yl)phenyl]methanesulfonamide 133 5-(3-ethylsulfonylphenyl)-7- Cmethylimidazo[1,5-a]pyrazin-8-one 134 N-[3-(5-chloro-1-methyl-6- A A A Boxopyridin-3-yl)-4-(2,4- difluorophenoxy)phenyl] ethane- sulfonamide 1354-[2-(cyclopropylmethoxy)-5- A A A B ethylsulfonylphenyl]-2-methylisoquinolin-1-one 136 6-[2-(cyclopropylmethoxy)-5- B C B Cmethylsulfonylphenyl]-2,4- dimethylpyridazin-3-one 1376-[2-(cyclopropylmethoxy)-5- B methylsulfonylphenyl]-2,5-dimethylpyridazin-3-one 138 N-[4-(2,4-difluorophenoxy)-3-[1- A A A Cmethyl-6-oxo-5- (trifluoromethyl)pyridin-3- yl] phenyl]ethanesulfonamide139 N-[4-(2,4-difluorophenoxy)-3-(4- A A A Cfluoro-1-methyl-6-oxopyridin-3- yl) phenyl]ethanesulfonamide 140N-[3-(5-cyclopropyl-1-methyl-6- A A A C oxopyridin-3-yl)-4-(2,4-difluorophenoxy) phenyl]ethane- sulfonamide 141N-{4-(2,4-difluorophenoxy)-3-[1- A (²H₃)methyl-6-oxopyridin-3-yl]phenyl} ethanesulfonamide 142 N-[4-(2,4-difluorophenoxy)-3-(2- Bmethyl-1-oxo-5,6,7,8-tetrahydro- 2,6-naph-thyridin-4- yl)phenyl]ethanesulfonamide 143 4-[5-(cyclopropylmethoxy)-2- A B B C(methylsulfonylmethyl)pyrimidin- 4-yl]-2-methylisoquinolin-1-one 1445-[5-(cyclopropylmethoxy)-2- A C B C (methylsulfonylmethyl)pyrimidin-4-yl]-1,3-dimethylpyridin-2-one 145 4-[5-(cyclopropylmethoxy)-2- A B A C(methylsulfonylmethyl)pyrimidin- 4-yl]-2-methyl-6-(1-methylpyrazol-4-yl) isoquinolin-1-one 146 5-[5-(2,4-difluorophenoxy)-2- A B C(methylsulfonylmethyl)pyrimidin- 4-yl]-3-methoxy-1-methylpyridin- 2-one147 5-[5-(2,4-difluorophenoxy)-2- A B C (methylsulfonylmethyl)pyrimidin-4-yl]-1,3-dimethylpyridin-2-one 148 4-[5-(2,4-difluorophenoxy)-2- A C(methylsulfonylmethyl)pyrimidin- 4-yl]-2-methylisoquinolin-1-one 1495-[5-(2,4-difluorophenoxy)-2- B C C C methylsulfonylpyrimidin-4-yl]-1,3-dimethylpyridin-2-one 150 5-[5-(2,4-difluorophenoxy)-2- A B B Cmethylsulfonylpyrimidin-4-yl]-3- methoxy-1-methylpyridin-2-one 1514-[5-(2,4-difluorophenoxy)-2- A methylsulfonylpyrimidin-4-yl]-2-methylisoquinolin-1-one 152 N-[5-(cyclopropylmethoxy)-4-(2- A A A Cmethyl-1-oxoisoquinolin-4- yl)pyrimidin-2-yl] methanesulfonamide 153N-[5-(cyclopropylmethoxy)-4-(1,5- A B B C dimethyl-6-oxopyridin-3-yl)pyrimidin-2- yl] methanesulfonamide 154N-[5-(cyclopropylmethoxy)-4-[2- A A A Cmethyl-6-(1-methylpyrazol-4-yl)-1- oxoisoquinolin-4-yl]pyrimidin-2- yl]methanesulfonamide 155 N-[5-(cyclopropylmethoxy)-4-(2- A A A Cmethyl-1-oxoisoquinolin-4- yl)pyrimidin-2- yl] ethanesulfonamide 1564-[5-(cyclopropylmethoxy)-2-(1,1- A dioxo-1,2-thiazolidin-2-yl)pyrimidin-4-yl]-2- methylisoquinolin-1-one 157N-[5-(cyclopropylmethoxy)-4-(6- A A A Cfluoro-2-methyl-1-oxoisoquinolin- 4-yl)pyrimidin-2- yl]ethanesulfonamide158 N-[5-(cyclopropylmethoxy)-4-(7- A A A Cfluoro-2-methyl-1-oxoisoquinolin- 4-yl)pyrimidin-2-yl]methanesulfonamide 159 N-[5-(cyclopropylmethoxy)-4-(6- A A A Cfluoro-2-methyl-1-oxoisoquinolin- 4-yl)pyrimidin-2-yl]methanesulfonamide 160 N-[5-(cyclopropylmethoxy)-4-(7- A A A Cfluoro-2-methyl-1-oxoisoquinolin- 4-yl)pyrimidin-2- yl]ethanesulfonamide161 N-[5-(cyclopropylmethoxy)-4-(2- A A A C methyl-1-oxoisoquinolin-4-yl)pyrimidin-2-yl]-N- ethylmethanesulfonamide 162N-[5-(cyclopropylmethoxy)-4-(1,5- A A A C dimethyl-6-oxopyridin-3-yl)pyrimidin-2-yl]-N- ethylmethanesulfonamide 163N-[5-(cyclopropylmethoxy)-4-(2- A A B C methyl-1-oxo-5,6,7,8-tetrahydroisoquinolin-4- yl)pyrimidin-2- yl]methanesulfonamide 164N-[5-(cyclopropylmethoxy)-4-(2- A A B C methyl-1-oxo-5,6,7,8-tetrahydroisoquinolin-4- yl)pyrimidin-2- yl]ethanesulfonamide 165N-[5-(2,4-difluorophenoxy)-4-(2- A B C methyl-1-oxoisoquinolin-4-yl)pyrimidin-2- yl]methanesulfonamide 166N-[5-(2,4-difluorophenoxy)-4-(1,5- A A A C dimethyl-6-oxopyridin-3-yl)pyrimidin-2- yl]methanesulfonamide 167N-[5-(2,4-difluorophenoxy)-4-(5- A B C methoxy-1-methyl-6-oxopyridin-3-yl) pyrimidin-2- yl]methanesulfonamide 168N-[5-(2,4-difluorophenoxy)-4-(5- A A A Cmethoxy-1-methyl-6-oxopyridin-3- yl) pyrimidin-2- yl]ethanesulfonamide169 N-[5-(2,4-difluorophenoxy)-4-(1,5- A A A Cdimethyl-6-oxopyridin-3-yl)pyrimidin- 2-yl] ethanesulfonamide 170N-[5-(2,4-difluorophenoxy)-4-(2- A A A C methyl-1-oxoisoquinolin-4-yl)pyrimidin-2- yl] ethanesulfonamide 1714-[5-(2,4-difluorophenoxy)-2-(1,1- A dioxo-1,2-thiazolidin-2-yl)pyrimidin-4-yl]-2- methylisoquinolin-1-one 172N-[5-(2,4-difluorophenoxy)-4-(2- A B B C methyl-1-oxo-5,6,7,8-tetrahydroisoquinolin-4- yl)pyrimidin-2- yl]methanesulfonamide 173N-[5-(2,4-difluorophenoxy)-4-(2- A B B C methyl-1-oxo-5,6,7,8-tetrahydroisoquinolin-4- yl)pyrimidin-2- yl]ethanesulfonamide 1744-[2-(cyclopropylmethoxy)-5- A A A C ethylsulfonylphenyl]-6-fluoro-2-methylisoquinolin-1-one 175 2-methyl-4-[5-methylsulfonyl-2- A A A C(oxolan-3- yloxy)phenyl]isoquinolin-1-one 1762-methyl-4-[5-methylsulfonyl-2- A A A C(oxan-4-yloxy)phenyl]isoquinolin- 1-one 177 4-(2-ethoxy-5- A B A Cmethylsulfonylphenyl)-2- methylisoquinolin-1-one 1782-methyl-4-(5-methylsulfonyl-2- A A A C propoxyphenyl)isoquinolin-1-one179 2-methyl-4-[5-methylsulfonyl-2- A A A C(oxan-3-yloxy)phenyl]isoquinolin- 1-one 180 4-[2-(trans-4- A A A Chydroxycyclohexyl)oxy-5- methylsulfonylphenyl]-2-methylisoquinolin-1-one 181 4-[5-ethylsulfonyl-2-(trans-4- A A A Chydroxycyclohexyl)oxyphenyl]-2- methylisoquinolin-1-one 1824-[2-(trans-4-aminocyclohexyl)oxy- A A A C 5-methylsulfonylphenyl]-2-methylisoquinolin-1-one 183 4-[2-(cis-4-aminocyclohexyl)oxy-5- A C B Cmethylsulfonylphenyl]-2- methylisoquinolin-1-one 184 4-(2-but-2-ynoxy-5-A B A B methylsulfonylphenyl)-2- methylisoquinolin-1-one 1854-(2-but-2-ynoxy-5- A A A C ethylsulfonylphenyl)-2-methylisoquinolin-1-one 186 6-fluoro-4-[2-(trans-4- A A A Chydroxycyclohexyl)oxy-5- methylsulfonylphenyl]-2-methylisoquinolin-1-one 187 7-fluoro-4-[2-(trans-4- A A A Chydroxycyclohexyl)oxy-5- methylsulfonylphenyl]-2-methylisoquinolin-1-one 188 4-[5-ethylsulfonyl-2-(trans-4- A Ahydroxycyclohexyl)oxyphenyl]-6- fluoro-2-methylisoquinolin-1-one 1894-[5-ethylsulfonyl-2-(trans-4- A A hydroxycyclohexyl)oxyphenyl]-7-fluoro-2-methylisoquinolin-1-one 190 2-methyl-4-[5-methylsulfonyl-2- A BB C (oxolan-3- ylamino)phenyl]isoquinolin-1-one 1912-methyl-4-[5-methylsulfonyl-2- A A A C (oxan-4-ylamino)phenyl]isoquinolin-1-one 192 4-[2-[(trans-4- A A A Chydroxycyclohexyl)amino]-5- methylsulfonylphenyl]-2-methylisoquinolin-1-one 193 4-[2-(cyclopropylmethylamino)-5- A A A Cethylsulfonylphenyl]-2- methylisoquinolin-1-one 1944-[2-(cyclopropylmethylamino)-5- A A A C methylsulfonylphenyl]-2-methylisoquinolin-1-one 195 4-[2-(cyclopropylmethylamino)-5- A A A Cethylsulfonylphenyl]-7-fluoro-2- methylisoquinolin-1-one 1964-[2-(cyclopropylmethylamino)-5- A A A Cmethylsulfonylphenyl]-7-fluoro-2- methylisoquinolin-1-one 1974-[2-(cyclopropylmethoxy)-5- A B C methylsulfonylphenyl]-2-methyl-6-(trifluoromethyl)isoquinolin-1-one 198 4-[2-(cyclopropylmethoxy)-5- A AA C methylsulfonylphenyl]-6-methoxy- 2-methylisoquinolin-1-one 1994-[3-(cyclopropylmethoxy)-6- A A A C methylsulfonylpyridin-2-yl]-2-methylisoquinolin-1-one 200 4-[5-(cyclopropylmethoxy)-2- A B A Cmethylsulfonylpyridin-4-yl]-2- methylisoquinolin-1-one 2014-[3-(cyclopropylmethoxy)-6- A A A C methylsulfonylpyridin-2-yl]-7-fluoro-2-methylisoquinolin-1-one 202 4-[3-(cyclopropylmethoxy)-6- A A Cmethylsulfonylpyridin-2-yl]-6- fluoro-2-methylisoquinolin-1-one 2034-[5-(cyclopropylmethoxy)-2- A A A C methylsulfonylpyridin-4-yl]-7-fluoro-2-methylisoquinolin-1-one 204 4-(2-ethoxy-5- A B B Cethylsulfonylthiophen-3-yl)-2- methylisoquinolin-1-one 2054-[2-(cyclopropylmethylamino)-5- A B B C ethylsulfonylthiophen-3-yl]-2-methylisoquinolin-1-one 206 4-[3-(cyclopropylmethoxy)-6- A A A Cethylsulfonylpyridin-2-yl]-2- methylisoquinolin-1-one 2074-[5-(cyclopropylmethoxy)-2- A A A C ethylsulfonylpyridin-4-yl]-2-methylisoquinolin-1-one 208 4-[5-(2-hydroxyethylsulfonyl)-2- A B A Cmethoxyphenyl]-2-methyl-6-(1- methylpyrazol-4-yl)isoquinolin-1- one 209N-[4-(cyclopropylmethoxy)-2- A A A C fluoro-5-[2-methyl-6-(1-methylpyrazol-4-yl)-1- oxoisoquinolin-4- yl]phenyl] ethanesulfonamide210 4-(5-ethylsulfonyl-2- A A A C methoxyphenyl)-2-methyl-6-(1H-pyrazol-4-yl) isoquinolin-1-one 211 4-(2-ethoxy-5- Amethylsulfonylphenyl)-2-methyl-6- (1-methylpyrazol-4-yl) isoquinolin-1-one 212 2-methyl-6-(1-methylpyrazol-4-yl)- A 4-(5-methylsulfonyl-2-propoxyphenyl) isoquinolin-1-one 213 N-[2-[2-methyl-6-(1- A B B Cmethylpyrazol-4-yl)-1- oxoisoquinolin-4-yl]pyridin-4- yl]ethanesulfonamide 214 [4-(cyclopropylmethoxy)-3-(2- A A A Cmethyl-1-oxoisoquinolin-4- yl)phenyl] sulfamate 215[4-(cyclopropylmethoxy)-3-(1,5- A A A C dimethyl-6-oxopyridin-3-yl)phenyl]sulfamate 216 4-(2-ethoxy-5- A methylsulfonylphenyl)-2-methyl-5,6,7,8-tetrahydroisoquinolin-1-one 217 4-[2-(cyclopropylmethoxy)-5- A AA C methylsulfonylphenyl]-2-methyl- 5,6,7,8-tetrahydroisoquinolin-1-one218 N-[4-(cyclopropylmethoxy)-2- A B A Cfluoro-5-(2-methyl-1-oxo-5,6,7,8- tetrahydroisoquinolin-4- yl)phenyl]methanesulfonamide 219 4-[2-(cyclopropylmethoxy)-5- A A A Cethylsulfonylphenyl]-2-methyl- 5,6,7,8-tetrahydroisoquinolin-1-one 220N-[2-(2-methyl-1-oxoisoquinolin-4- B C C C yl)-4- methylsulfonylphenyl]cyclo- propanecarboxamide 221 N-[2-(2-methyl-1-oxoisoquinolin-4- C C C Cyl)-4- methylsulfonylphenyl]propanamide 222N-[2-(2-methyl-1-oxoisoquinolin-4- C C C C yl)-4-methylsulfonylphenyl]acetamide 223 4-[2-(cyclopropylmethylamino)-5- A BA C methylsulfonylphenyl]-2-methyl- 5,6,7,8-tetrahydroisoquinolin-1-one224 8-[2-(cyclopropylmethoxy)-5- A A A Cmethylsulfonylphenyl]-6-methyl-2- (1-methylpyrazol-4-yl)pyrido[4,3- d]pyrimidin-5-one 225 8-(5-ethylsulfonyl-2- A A A Cpropoxyphenyl)-6-methyl-2-(1- methylpyrazol-4-yl) pyrido[4,3-d]pyrimidin-5-one 226 8-[2-(cyclopropylmethoxy)-5- A A A Cethylsulfonylphenyl]-6-methyl-2- (1-methylpyrazol-4-yl)pyrido[4,3-d]pyrimidin-5-one 227 8-(2-ethoxy-5- A B A Cethylsulfonylphenyl)-6-methyl-2- (1-methylpyrazol-4-yl)pyrido[4,3-d]pyrimidin-5-one 228 6-methyl-2-(1-methylpyrazol-4-yl)- A B A C8-(5-methylsulfonyl-2- propoxyphenyl)pyrido[4,3- d]pyrimidin-5-one 229N-[4-(2,4-difluorophenoxy)-3-(1,5- A A A Cdimethyl-6-oxopyridin-3-yl)phenyl]-N- methylmethanesulfonamide 230N-[4-(2,4-difluorophenoxy)-3-(1,5- A A A C dimethyl-6-oxopyridin-3-yl)phenyl]-N-(oxetan-3- yl)methanesulfonamide 2318-[2-(cyclopropylmethoxy)-5- B methylsulfonylphenyl]-6-methylpyrido[4,3-d]pyrimidin-5- one 232 8-[2-(cyclopropylmethoxy)-5- Aethylsulfonylphenyl]-6- methylpyrido[4,3-d] pyrimidin-5- one 2338-[2-(2,4-difluorophenoxy)-5- B methylsulfonylphenyl]-6-methylpyrido[4,3-d]pyrimidin-5- one 234 8-[2-(2,4-difluorophenoxy)-5- Bethylsulfonylphenyl]-6- methylpyrido[4,3-d] pyrimidin-5- one 2355-[2-(cyclopropylmethoxy)-5- C C C C methylsulfonylphenyl]-7-methyl-[1,2,4]triazolo[4,3-a]pyrazin-8-one 236 N-[4-(2,4-difluorophenoxy)-3-(7-A C B C methyl-8-oxo-[1,2,4]triazolo[4,3- a]pyrazin-5-yl)phenyl]ethanesulfonamide 237 7-[2-(cyclopropylmethoxy)-5- Amethylsulfonylphenyl]-5-methyl- [1,3]oxazolo[4,5-c]pyridin-4-one 2387-[2-(cyclopropylmethoxy)-5- A B A C methylsulfonylphenyl]-2,5-dimethyl-[1,3]oxazolo[4,5- c]pyridin-4-one 239 5-methyl-7-[5- A(methylsulfonylmethyl)-2-(2,2,2- trifluoroethoxy)phenyl]-[1,3]oxazolo[4,5-c]pyridin-4-one 240 N-[4-(2,4-difluorophenoxy)-3-(5- AA A C methyl-4-oxo-[1,3]oxazolo[4,5- c]pyridin-7- yl)phenyl]ethanesulfonamide 241 N-[4-(2,4-difluorophenoxy)-3-(2,5- A A A Cdimethyl-4-oxo-[1,3]oxazolo[4,5- c]pyridin-7-yl)phenyl]ethanesulfonamide 242 5-[2-(cyclopropylmethoxy)-5- A B A Cmethylsulfonylphenyl]-1- (cyclopropylmethyl)-3- methylpyridin-2-one 2435-[2-(cyclopropylmethoxy)-5- B C B C methylsulfonylphenyl]-3-methyl-1-(2-methylpropyl)pyridin-2-one 244 5-[2-(cyclopropylmethoxy)-5- B C B Cmethylsulfonylphenyl]-1-(2- methoxyethyl)-3-methylpyridin-2- one 2455-[2-(cyclopropylmethoxy)-5- B C C C methylsulfonylphenyl]-3-methyl-1-(oxetan-3-ylmethyl)pyridin-2-one 246 5-[2-(cyclopropylmethoxy)-5- B C CC methylsulfonylphenyl]-3-methyl-1- (1,3-oxazol-4-ylmethyl)pyridin-2-one 247 N-[3-[1-(cyclopropylmethyl)-5- A A A Cmethyl-6-oxopyridin-3-yl]-4-(2,4- difluorophenoxy) phenyl]ethane-sulfonamide 248 N-[4-[1-(cyclopropylmethyl)-5- A A A Cmethyl-6-oxopyridin-3-yl]-5-(2,4- difluorophenoxy) pyrimidin-2-yl]methanesulfonamide 249 N-[4-[1-(cyclopropylmethyl)-5- A A A Cmethyl-6-oxopyridin-3-yl]-5-(2,4- difluorophenoxy)pyrimidin-2-yl]ethanesulfonamide 250 1-(cyclopropylmethyl)-5-[4-(2,4- A B A Cdifluorophenoxy)-1- (methylsulfonylmethyl)-6-oxopyridin-3-yl]-3-methylpyridin- 2-one 251 1-cyclopropyl-5-[2- A B A C(cyclopropylmethoxy)-5- ethylsulfonylphenyl]-3- methylpyridin-2-one 2524-[2-(cyclopropylmethoxy)-5- A A A C ethylsulfonylphenyl]-6-methylfuro[2,3-c]pyridin-7-one 253 N-[4-(2,4-difluorophenoxy)-3-(6- A AA C methyl-7-oxofuro[2,3-c]pyridin-4- yl)phenyl]ethanesulfonamide 2544-[2-(cyclopropylmethoxy)-5- A A A C methylsulfonylphenyl]-6-methylfuro[2,3-c]pyridin-7-one 255 N-[4-(cyclopropylmethoxy)-3-(6- A A AC methyl-7-oxofuro[2,3-c]pyridin-4- yl) phenyl]ethanesulfonamide 256N-[6-(2,4-difluorophenoxy)-5-(6- A A A Cmethyl-7-oxofuro[2,3-c]pyridin-4- yl)pyridin-3-yl]ethanesulfonamide 257N-[6-(cyclopropylmethoxy)-5-(6- A A A Cmethyl-7-oxofuro[2,3-c]pyridin-4- yl)pyridin-3-yl]ethanesulfonamide 2586-methyl-4-[5- A B A B (methylsulfonylmethyl)-2-(2,2,2-trifluoroethoxy)phenyl]furo[2,3- c] pyridin-7-one 2594-[3-(cyclopropylmethoxy)-6- A B A C methylsulfonylpyridin-2-yl]-6-methylfuro[2,3-c]pyridin-7-one 260 2-chloro-4-[2- A A A B(cyclopropylmethoxy)-5- methylsulfonylphenyl]-6-methylfuro[2,3-c]pyridin-7-one 261 N-[6-(cyclopropylmethoxy)-5-(2- A A AC fluoro-6-methyl-7-oxofuro[2,3- c]pyridin-4-yl)pyridin-3-yl]ethanesulfonamide 262 N-[5-(2,4-difluorophenoxy)-4-(6- A A A Cmethyl-7-oxofuro[2,3-c]pyridin-4- yl)pyrimidin-2- yl]methanesulfonamide263 N-[5-(2,4-difluorophenoxy)-4-(6- A A A Cmethyl-7-oxofuro[2,3-c]pyridin-4- yl)pyrimidin-2- yl]ethanesulfonamide264 N-[5-(cyclopropylmethoxy)-4-(6- A A A Cmethyl-7-oxofuro[2,3-c]pyridin-4- yl)pyrimidin-2- yl]ethanesulfonamide265 4-[2-(cyclopropylmethoxy)-5- A A A Cethylsulfonylphenyl]-6-methyl-7- oxothieno[2,3-c]pyridine-2- carboxamide266 4-[2-(cyclopropylmethoxy)-5- A A A C (ethylsulfonylamino)phenyl]-6-methyl-7-oxothieno[2,3-c]pyridine- 2-carboxamide 2674-[2-(cyclopropylmethoxy)-5- A B A C methylsulfonylphenyl]-6-methyl-7-oxothieno[2,3-c]pyridine-2- carboxamide 268 4-[2-(cyclopropylmethoxy)-5-A B A C (ethylsulfonylamino)pyridin-3-yl]- 6-methyl-7-oxothieno[2,3-c]pyridine-2-carboxamide 269 N-[4-(2,4-difluorophenoxy)-3-(2,6- A A A Cdimethyl-7-oxofuro[2,3-c]pyridin- 4-yl)phenyl]ethanesulfonamide 2704-[2-(cyclopropylmethoxy)-5- A A A B ethylsulfonylphenyl]-2,6-dimethylfuro[2,3-c]pyridin-7-one 271 N-[4-(2,4-difluorophenoxy)-3-(5- AA A C fluoro-1-methyl-6-oxopyridin-3- yl)phenyl] methanesulfonamide 2723-chloro-5-[2- A A A C (cyclopropylmethoxy)-5- ethylsulfonylphenyl]-1-methylpyridin-2-one 273 5-[5-(2,4-difluorophenoxy)-2- Bmethylsulfonylpyrimidin-4-yl]-1- methyl-3-propan-2-ylpyridin-2-one 2745-[2-(cyclopropylmethoxy)-5- A B B C ethylsulfonylphenyl]-3-fluoro-1-methylpyridin-2-one 275 3-chloro-5-[2- A A A C(cyclopropylmethylamino)-5- ethylsulfonylphenyl]-1- methylpyridin-2-one276 5-[2-(2,4-difluorophenoxy)-5- A A (methanesulfonylmethyl)phenyl]-3-(²H₃)methyl-1-methyl-1,2- dihydropyridin-2-one 277N-[4-(2,4-difluorophenoxy)-3-[5- A A (²H₃)methyl-1-methyl-6-oxo-1,6-dihydropyridin-3- yl]phenyl] methanesulfonamide 278N-[4-(2,4-difluorophenoxy)-3-[5- A A (²H₃)methyl-1-methyl-6-oxo-1,6-dihydropyridin-3-yl]phenyl] ethane- 1-sulfonamide 279N-[3-(5-cyclopropyl-1-methyl-6- A A A C oxopyridin-3-yl)-4-(2,4-difluorophenoxy)phenyl]methane- sulfonamide 280 3-cyclopropyl-5-[2- A AA C (cyclopropyl-methoxy)-5- ethylsulfonylphenyl]-1- methylpyridin-2-one281 N-[4-(2,4-difluorophenoxy)-3-(1- B methyl-6-oxo-5-pyrrolidin-1-ylpyridin-3- yl)phenyl]methanesulfonamide 2825-[2-(cyclopropylmethoxy)-5- B ethylsulfonylphenyl]-1-methyl-3-pyrrolidin-1-ylpyridin-2-one 283 N-[4-(2,4-difluorophenoxy)-3-(5- A B AC ethynyl-1-methyl-6-oxopyridin-3- yl)phenyl]ethanesulfonamide 2845-[2-(cyclopropylmethoxy)-5- A B B C ethylsulfonylphenyl]-3-ethynyl-1-methylpyridin-2-one 285 5-[2-(cyclopropylmethoxy)-5- Bmethylsulfonylphenyl]-3-ethynyl-1- methylpyridin-2-one 286N-[4-(2,4-difluorophenoxy)-3-(5- A B C ethynyl-1-methyl-6-oxopyridin-3-yl) phenyl]methanesulfonamide 287 5-[2-(cyclopropylmethoxy)-5- A B A Cethylsulfonylphenyl]-3- (difluoromethoxy)-1- methylpyridin-2-one 2885-[2-(cyclopropylmethoxy)-5- A B ethylsulfonylphenyl]-1-methyl-3-(2,2,2-trifluoroethoxy)pyridin-2-one 289 N-[3-[5-(difluoromethoxy)-1- AA A C methyl-6-oxopyridin-3-yl]-4-(2,4- difluorophenoxy) phenyl]ethane-sulfonamide 290 N-[4-(2,4-difluorophenoxy)-3-[1- A A A Cmethyl-6-oxo-5-(2,2,2- trifluoroethoxy)pyridin-3- yl]phenyl]ethanesulfonamide 291 3-(difluoromethoxy)-5-[2-(2,4- A A A Cdifluorophenoxy)-5- (ethylsulfonylmethyl) phenyl]-1- methylpyridin-2-one292 5-[2-(2,4-difluorophenoxy)-5- A B A C(ethylsulfonylmethyl)phenyl]-1- methyl-3-(2,2,2-trifluoroethoxy)pyridin-2-one 293 5-[2-(cyclopropylmethoxy)-5- A B B Cmethylsulfonylphenyl]-1-methyl-3- (1-methylpyrazol-4-yl)oxypyridin-2-one 294 5-[2-(cyclopropylmethoxy)-5- A C B Cmethylsulfonylphenyl]-1-methyl-3- (1-propan-2-ylpyrazol-4-yl)oxypyridin-2-one 295 5-[2-(cyclopropylmethoxy)-5- A B B Bmethylsulfonylphenyl]-1-methyl-3- phenoxypyridin-2-one 296N-[4-(1-butyl-5-methyl-6- A oxopyridin-3-yl)-5-(2,4-difluorophenoxy)pyrimidin-2- yl]methanesulfonamide 297N-[4-(1-butyl-5-methyl-6- A oxopyridin-3-yl)-5-(2,4-difluorophenoxy)pyrimidin-2- yl]ethanesulfonamide 298N-[4-[1-(cyclobutylmethyl)-5- B methyl-6-oxopyridin-3-yl]-5-(2,4-difluorophenoxy)pyrimidin-2- yl]methanesulfonamide 299N-[4-[1-(cyclobutylmethyl)-5- B methyl-6-oxopyridin-3-yl]-5-(2,4-difluorophenoxy)pyrimidin-2- yl]ethanesulfonamide 300N-[5-ethyl-4-(2-methyl-1- A oxoisoquinolin-4-yl)pyrimidin-2-yl]ethanesulfonamide 301 2-methyl-4-(2-methylsulfonyl-5-propylpyrimidin-4-yl)isoquinolin-1- one 302 5-(5-ethyl-2-methylsulfonylpyrimidin-4-yl)-1,3- dimethylpyridin-2-one 3031,3-dimethyl-5-(2-methylsulfonyl- 5-propylpyrimidin-4-yl)pyridin-2- one304 4-(5-butyl-2- A methylsulfonylpyrimidin-4-yl)-2-methylisoquinolin-1-one 305 5-(5-butyl-2- Amethylsulfonylpyrimidin-4-yl)-1,3- dimethylpyridin-2-one 306N-[4-(2-methyl-1-oxoisoquinolin-4- A yl)-5-propylpyrimidin-2-yl]ethanesulfonamide 307 N-[4-(1,5-dimethyl-6-oxopyridin-3- A A A Cyl)-5-ethylpyrimidin-2- yl]ethanesulfonamide 308N-[4-(1,5-dimethyl-6-oxopyridin-3- A A A C yl)-5-propylpyrimidin-2-yl]ethanesulfonamide 309 N-[5-butyl-4-(2-methyl-1- A A A Coxoisoquinolin-4-yl)pyrimidin-2- yl] ethanesulfonamide 310N-[5-butyl-4-(1,5-dimethyl-6- A A A C oxopyridin-3-yl)pyrimidin-2-yl]ethanesulfonamide 311 4-[5-(cyclopropylmethoxy)-2- Amethylsulfonylpyrimidin-4-yl]-2- methylisoquinolin-1-one 3125-(2-ethyl-5- B C C C methylsulfonylphenyl)-1- methylpyridin-2-one 3131-methyl-5-(5-methylsulfonyl-2- B C B C propylphenyl)pyridin-2-one 3142-methyl-4-(5-methylsulfonyl-2- A propylphenyl)isoquinolin-1-one 3155-[2-(2-cyclopropylethyl)-5- A methylsulfonylphenyl]-1-methylpyridin-2-one 316 4-(2-ethyl-5- A methylsulfonylphenyl)-2-methylisoquinolin-1-one 317 5-(2-butyl-5- A methylsulfonylphenyl)-1-methylpyridin-2-one 318 4-(2-butyl-5- A methylsulfonylphenyl)-2-methylisoquinolin-1-one 319 4-[2-(2-cyclopropylethyl)-5- Amethylsulfonylphenyl]-2- methylisoquinolin-1-one 320N-[6-(cyclopropylmethoxy)-5-(2- A A A C methyl-1-oxoisoquinolin-4-yl)pyridin-3-yl]ethanesulfonamide 321 4-[2-(cyclopropylmethoxy)-5- A A AC methylsulfonylpyridin-3-yl]-2- methylisoquinolin-1-one 3224-[2-(cyclopropylmethoxy)-5- A A A C ethylsulfonylpyridin-3-yl]-2-methylisoquinolin-1-one 323 5-[3-[(4-methoxyphenyl)methoxy]- A5-methylsulfonylphenyl]-1,3- dimethylpyridin-2-one 3241,3-dimethyl-5-(3-methylsulfonyl- A B A C5-phenylmethoxyphenyl)pyridin-2- one 325 5-[3-(cyclopropylmethoxy)-5- AB B C methylsulfonylphenyl]-1,3- dimethylpyridin-2-one 3261,3-dimethyl-5-[3-methylsulfonyl- A B B C5-(2-phenylethoxy)phenyl]pyridin- 2-one 3275-[3-(2-cyclopropylethoxy)-5- A B B C methylsulfonylphenyl]-1,3-dimethylpyridin-2-one 328 1,3-dimethyl-5-[3-methylsulfonyl- A 5-(2,2,2-trifluoroethoxy)phenyl] pyridin-2- one 329 1,3-dimethyl-5-[3-[(3- Amethyloxetan-3-yl)methoxy]-5- methylsulfonylphenyl]pyridin-2- one 3301,3-dimethyl-5-[3-methylsulfonyl- A 5-(pyridin-2- ylmethoxy) phenyl]pyridin-2-one 331 5-[3-[(2,6- A B A C dimethylphenyl)methoxy]-5-methylsulfonylphenyl]-1,3- dimethylpyridin-2-one 3325-[3-[(2-chlorophenyl)methoxy]-5- A methylsulfonylphenyl]-1,3-dimethylpyridin-2-one 333 5-[3-[[2- A B A C(difluoromethoxy)phenyl]methoxy]- 5-methylsulfonylphenyl]-1,3-dimethylpyridin-2-one 334 2-[[3-(l,5-dimethyl-6-oxopyridin- A B A C3-yl)-5-methylsulfonyl- phenoxy] methyl]benzonitrile 335 5-[3-[(2,4- Adifluorophenyl)methoxy]-5- methylsulfonylphenyl]-1,3-dimethylpyridin-2-one 336 1,3-dimethyl-5-[3-methylsulfonyl- A B A C5-(1-phenylethoxy)phenyl]pyridin- 2-one 337 5-[3-[(2,3- Bdichlorophenyl)methoxy]-5- methylsulfonylphenyl]-1,3-dimethylpyridin-2-one 338 1,3-dimethyl-5-[3-methylsulfonyl- A5-(pyridin-3- ylmethoxy) phenyl]pyridin-2-one 3393-[[3-(1,5-dimethyl-6-oxopyridin-3- A yl)-5-methylsulfonyl-phenoxy]methyl] benzonitrile 340 5-(3-but-2-ynoxy-5- Amethylsulfonylphenyl)-1,3- dimethylpyridin-2-one 3411,3-dimethyl-5-[3-methylsulfonyl- A A A C5-(1-phenylethoxy)phenyl]pyridin- 2-one 342N-[3-(2,4-difluorophenoxy)-5-(1,5- A A A B dimethyl-6-oxopyridin-3- yl)phenyl]ethanesulfonamide 343 4-[3-[(4-methoxyphenyl)methoxy]- B5-methylsulfonylphenyl]-2- methylisoquinolin-1-one 3442-methyl-4-(3-methylsulfonyl-5- A phenylmethoxyphenyl)isoquinolin- 1-one345 4-[3-(cyclopropylmethoxy)-5- A methylsulfonylphenyl]-2-methylisoquinolin-1-one 346 N-[4-(2,4-difluorophenoxy)-6-(1,5- Bdimethyl-6-oxopyridin-3- yl)pyrimidin-2- yl]ethanesulfonamide 347N-[2-(2,4-difluorophenoxy)-6-(1,5- B dimethyl-6-oxopyridin-3-yl)pyrimidin-4- yl]ethanesulfonamide 348 4-[3-[[2- A A A B(difluoromethoxy)phenyl] methoxy]- 5-methylsulfonylphenyl]-6-methylfuro[2,3-c]pyridin-7-one 349 6-methyl-4-(3-methylsulfonyl-5- A A AC phenylmethoxyphenyl)furo[2,3- c]pyridin-7-one 3504-[3-(cyclopropylmethoxy)-5- A methylsulfonylphenyl]-6-methylfuro[2,3-c]pyridin-7-one 351 1-methyl-5-(2-methylsulfonyl-5-propylpyrimidin-4-yl)pyridin-2-one 352 5-(5-butyl-2-methylsulfonylpyrimidin-4-yl)-1- methylpyridin-2-one 3533-chloro-1-methyl-5-(2- methylsulfonyl-5-propylpyrimidin-4-yl)pyridin-2-one 354 5-(5-butyl-2- methylsulfonylpyrimidin-4-yl)-3-chloro-1-methylpyridin-2-one 355 3-methoxy-1-methyl-5-(2-methyl-sulfonyl-5-propylpyrimidin- 4-yl) pyridin-2-one 356 5-(5-butyl-2-methylsulfonylpyrimidin-4-yl)-3- methoxy-1-methylpyridin-2-one 357N-[4-(1-methyl-6-oxopyridin-3-yl)- A 5-propylpyrimidin-2-yl]ethanesulfonamide 358 N-[5-butyl-4-(1-methyl-6- Aoxopyridin-3-yl)pyrimidin-2- yl]ethanesulfonamide 359N-[4-(5-chloro-1-methyl-6- A oxopyridin-3-yl)-5- propylpyrimidin-2- yl]ethanesulfonamide 360 N-[5-butyl-4-(5-chloro-1-methyl-6- Aoxopyridin-3-yl)pyrimidin-2- yl] ethanesulfonamide 361N-[4-(5-methoxy-1-methyl-6- A oxopyridin-3-yl)-5- propylpyrimidin-2- yl]ethanesulfonamide 362 N-[5-butyl-4-(5-methoxy-1-methyl- A6-oxopyridin-3-yl)pyrimidin-2- yl] ethanesulfonamide 363N-[5-butyl-4-(1,5-dimethyl-6- A oxopyridin-3-yl)pyrimidin-2-yl]methanesulfonamide 364 4-[2-(cyclopropylmethoxy)-5- Apropan-2-ylsulfonylphenyl]-2- methylisoquinolin-1-one 3658-[2-(cyclopropylmethoxy)-5- A A A C ethylsulfonylphenyl]-6-methyl-4H-pyrido[4,3-b][1,4]oxazine-3,5-dione 366 8-[2-(cyclopropylmethoxy)-5- Aethylsulfonylphenyl]-6-methyl-3,4- dihydro-2H-pyrido[4,3- b][1,4]oxazin-5-one 367 N-[4-(2,4-difluorophenoxy)-3-(7- A A A Cmethyl-8-oxoimidazo[1,5- a]pyrazin-5- yl)phenyl]methanesulfonamide 3685-[2-(cyclopropylmethoxy)-5- A A A B ethylsulfonylphenyl]-7-methylimidazo[1,5-a]pyrazin-8-one 369 5-[2-(2,4-difluorophenoxy)-5- A BA C (ethylsulfonylmethyl)phenyl]-7- methylimidazo[1,5-a]pyrazin-8-one370 7-methyl-5-[5- A B B C (methylsulfonylmethyl)-2-(2,2,2-trifluoroethoxy)phenyl] imidazo[1,5- a]pyrazin-8-one 3715-[5-(ethylsulfonylmethyl)-2- B B B C (2,2,2-trifluoroethoxy)phenyl]-7-methylimidazo[1,5-a]pyrazin-8-one 372 5-[2-(2,4-difluorophenoxy)-5- A AA C (methylsulfonylmethyl)phenyl]-7- methylimidazo[1,5-a]pyrazin-8-one373 5-[2-(4,4-difluorocyclohexyl)oxy-5- A B A C ethylsulfonylphenyl]-7-methylimidazo[1,5-a]pyrazin-8-one 374 5-(2-cyclopentyloxy-5- A A A Cethylsulfonylphenyl)-7- methylimidazo[1,5-a]pyrazin-8-one 3755-[2-(cyclopropylmethylamino)-5- A ethylsulfonylphenyl]-7-methylimidazo[1,5-a]pyrazin-8-one 376 5-[2-(2,4-difluorophenoxy)-5- A BA C ethylsulfonylphenyl]-7- methylimidazo[1,5-a]pyrazin-8-one 3777-[2-(cyclopropylmethoxy)-5- A A A C methylsulfonylphenyl]-5-methylfuro[3,2-c]pyridin-4-one 378 7-[2-(cyclopropylmethoxy)-5- A A A Bethylsulfonylphenyl]-5- methylfuro[3,2-c] pyridin-4-one 379N-[4-(2,4-difluorophenoxy)-3-(5- A A A Cmethyl-4-oxofuro[3,2-c]pyridin-7- yl)phenyl] ethanesulfonamide 380N-[4-(2,4-difluorophenoxy)-3-(5- A A A Cmethyl-4-oxofuro[3,2-c]pyridin-7- yl)phenyl] methanesulfonamide 3814-(cyclopropylmethoxy)-5-(1- A C B C methyl-6-oxopyridin-3-yl)-1-(methylsulfonylmethyl)pyridin-2-one 382 5-[4-(cyclopropylmethoxy)-1- A BA C (methylsulfonylmethyl)-6- oxopyridin-3-yl]-1,3-dimethylpyridin-2-one 383 4-[4-(cyclopropylmethoxy)-1- A B A C(methylsulfonylmethyl)-6- oxopyridin-3-yl]-7-fluoro-2-methylisoquinolin-1-one 384 4-[4-(cyclopropylmethoxy)-1- A B A C(methylsulfonylmethyl)-6- oxopyridin-3-yl]-2- methylisoquinolin-1-one385 5-[4-(2,4-difluorophenoxy)-1- A A A C (methylsulfonylmethyl)-6-oxopyridin-3-yl]-1,3- dimethylpyridin-2-one 3864-(2,4-difluorophenoxy)-5-(1- A B B C methyl-6-oxopyridin-3-yl)-1-(methylsulfonylmethyl)pyridin-2- one 387 4-[4-(2,4-difluorophenoxy)-1- AA A C (methylsulfonylmethyl)-6- oxopyridin-3-yl]-2-methylisoquinolin-1-one 388 5-(2-but-2-ynoxy-5- A A A Cmethylsulfonylphenyl)-1,3- dimethylpyridin-2-one 389 5-(2-but-2-ynoxy-5-A B A C ethylsulfonylphenyl)-3-methoxy-1- methylpyridin-2-one 3905-(5-ethylsulfonyl-2-pent-2- A ynoxyphenyl)-3-methoxy-1-methylpyridin-2-one 391 5-[2-(3-cyclopropylprop-2-ynoxy)- A B A C5-ethylsulfonylphenyl]-3-methoxy- 1-methylpyridin-2-one 3925-[2-(2,4-difluorophenoxy)-5- B ethylsulfonylphenyl]-1-methyl-3-(trifluoromethyl)pyridin-2-one 393 4-[2-(cyclopropylmethoxy)-5- Apropan-2-ylsulfonylphenyl]-6- methoxy-2-methylisoquinolin-1- one 3945-[2-(cyclopropylmethoxy)-5- A propan-2-ylsulfonylphenyl]-1,3-dimethylpyridin-2-one 395 N-[3-(1,5-dimethyl-6-oxopyridin-3- A yl)-5-phenylmethoxyphenyl]ethanesulfonamide 396 5-[2-(2,4-difluoroanilino)-5-A A A C ethylsulfonylphenyl]-1,3- dimethylpyridin-2-one 397 5-[2-[(4,4-A A A C difluorocyclohexyl)amino]-5- ethylsulfonylphenyl]-1,3-dimethylpyridin-2-one 398 5-[2-(2,4-difluoroanilino)-5- A B A Cmethylsulfonylphenyl]-1,3- dimethylpyridin-2-one 3995-[2-(cyclopropylmethoxy)-5- A A A C ethylsulfonylphenyl]-3-methoxy-1-methylpyridin-2-one 400 5-[2-(2,4-difluorophenoxy)-5- A A A C(methylsulfonylmethyl)phenyl]-3- methoxy-1-methylpyridin-2-one 4015-[2-(4-hydroxycyclohexyl)oxy-5- A B A C methylsulfonylphenyl]-1,3-dimethylpyridin-2-one 402 N-[4-(2,4-difluorophenoxy)-3-(1- A A A Cmethyl-5-methylsulfanyl-6- oxopyridin-3- yl)phenyl]ethanesulfonamide 4035-[2-(cis-4-aminocyclohexyl)oxy-5- A methylsulfonylphenyl]-1,3-dimethylpyridin-2-one 404 5-[2-(trans-4-aminocyclohexyl)oxy- A C A C5-methylsulfonylphenyl]-1,3- dimethylpyridin-2-one 4051,3-dimethyl-5-[5-methylsulfonyl- A 2-(3,3,3- trifluoropropoxy)phenyl]pyridin-2-one 406 5-[2-(2,4-difluorophenoxy)-5- A(methylsulfonylmethyl)phenyl]-1- (2-hydroxyethyl)-3-methylpyridin- 2-one407 5-[5-(ethylsulfonylmethyl)-2- B (2,2,2-trifluoroethoxy)phenyl]-1-(2-hydroxyethyl)-3-methylpyridin-2- one 4085-[2-(cyclopropylmethylamino)-5- A ethylsulfonylphenyl]-1-methyl-3-(methylamino)pyridin-2-one 409 5-[2-(cyclopropylmethoxy)-5- Aethylsulfonylphenyl]-1-methyl-3- (methylamino)pyridin-2-one 410N-[4-(2,4-difluorophenoxy)-3-[1- A methyl-5-(methylamino)-6-oxopyridin-3- yl]phenyl]ethanesulfonamide 4115-[5-(ethylsulfonylmethyl)-2- A (2,2,2-trifluoroethoxy)phenyl]-1,3-dimethylpyridin-2-one 412 N-[4-(2,4-difluorophenoxy)-3-[1- Amethyl-5-(methylamino)-6- oxopyridin-3- yl]phenyl]methanesulfonamide 4135-[2-[(4,4- A difluorocyclohexyl)amino]-5- methylsulfonylphenyl]-1,3-dimethylpyridin-2-one 414 5-[2-(cyclopropylmethylamino)-5- Aethylsulfonylphenyl]-3-methoxy-1- methylpyridin-2-one 4155-[2-(4,4-difluorocyclohexyl)oxy-5- A A A C methylsulfonylphenyl]-1,3-dimethylpyridin-2-one 416 5-[2-(cyclopentylamino)-5- A A A Cethylsulfonylphenyl]-1,3- dimethylpyridin-2-one 4175-[2-(cyclopentylamino)-5- A A A C methylsulfonylphenyl]-1,3-dimethylpyridin-2-one 418 3-chloro-1-methyl-5-[5- A B A C(methylsulfonylmethyl)-2-(2,2,2- trifluoroethoxy)phenyl]pyridin-2-one419 5-(2-cyclopentyloxy-5- A B A C methylsulfonylphenyl)-1,3-dimethylpyridin-2-one 420 1,3-dimethyl-5-[5-methylsulfonyl- A B A C2-(oxan-4-yloxy)phenyl]pyridin-2-one 421 3-fluoro-1-methyl-5-[5- A(methylsulfonylmethyl)-2-(2,2,2- trifluoroethoxy)phenyl]pyridin-2-one422 5-[2-(cyclopropylmethylamino)-5- B methylsulfonylphenyl]-1,4-dimethylpyridin-2-one 423 5-[2-(cyclopropylmethylamino)-5- Bethylsulfonylphenyl]-1,4- dimethylpyridin-2-one 424N-[4-(1-methyl-6-oxopyridin-3-yl)- C 5-phenylthiophen-2-yl]ethanesulfonamide 425 1,3-dimethyl-5-[5-methylsulfonyl- A2-(oxolan-3- ylamino)phenyl]pyridin-2-one 4261,3-dimethyl-5-[5-methylsulfonyl- A B B C2-(oxolan-3-yloxy)phenyl]pyridin- 2-one 427 1,3-dimethyl-5-[5- A A A C(methylsulfonylmethyl)-2-(2,2,2- trifluoroethoxy)phenyl]pyridin-2-one428 5-[2-(cyclopropylmethylamino)-5- A B B Cmethylsulfonylphenyl]-1-ethyl-3- methylpyridin-2-one 4295-[2-(2,4-difluorophenoxy)-5- A A A C (methylsulfonylmethyl)phenyl]-1-ethyl-3-methylpyridin-2-one 430 N-[3-(1,5-dimethyl-6-oxopyridin-3- A A AC yl)-4-(trans-4-hydroxycyclohexyl)oxy- phenyl]ethanesulfonamide 431N-[3-(1,5-dimethyl-6-oxopyridin-3- A B A Cyl)-4-(cis-4-hydroxycyclohexyl) oxyphenyl]ethanesulfonamide 432N-[4-(1-methyl-6-oxopyridin-3-yl)- C 5-(2-methylphenyl)thiophen-2-yl]ethanesulfonamide 433 N-[3-(1,5-dimethyl-6-oxopyridin-3- A A A Cyl)-4-(trans-4- hydroxycyclohexyl) oxyphenyl]methane- sulfonamide 434N-[3-(1,5-dimethyl-6-oxopyridin-3- A B B C yl)-4-(cis-4-hydroxycyclohexyl)oxyphenyl] methane- sulfonamide 435N-[5-(2-ethylphenyl)-4-(1-methyl- C 6-oxopyridin-3-yl)thiophen-2- yl]ethanesulfonamide 436 1,3-dimethyl-5-[5-methylsulfonyl- A B A C2-(oxan-4-ylamino)phenyl]pyridin- 2-one 4375-[2-(2,4-difluorophenoxy)-5- A A A C (methylsulfonylmethyl)phenyl]-3-fluoro-1-methylpyridin-2-one 438 5-[2-(cyclopropylmethylamino)-5- A A AC methylsulfonylphenyl]-3- (dimethylamino)-1-methylpyridin- 2-one 439N-[3-(1,5-dimethyl-6-oxopyridin-3- A A A C yl)-4-(oxan-4- yloxy)phenyl]methanesulfonamide 440 5-[2-(cyclopropylmethylamino)-5- A A A Cethylsulfonylphenyl]-3- (dimethylamino)-1-methylpyridin- 2-one 441N-[3-(1,5-dimethyl-6-oxopyridin-3- A A A C yl)-4-(oxan-4-yloxy)phenyl]ethanesulfonamide 442 N-[4-(2,4-difluorophenoxy)-3-(5- A AA C methoxy-1-methyl-6-oxopyridin-3- yl)phenyl]methanesulfonamide 443N-[4-(2,4-difluorophenoxy)-3-(5- A A A Cmethoxy-1-methyl-6-oxopyridin-3- yl)phenyl]ethanesulfonamide 444N-[3-(1,5-dimethyl-6-oxopyridin-3- A A A C yl)-4-(oxolan-3-yloxy)phenyl] methanesulfonamide 445 N-[3-(1,5-dimethyl-6-oxopyridin-3-A A A C yl)-4-(oxolan-3- yloxy)phenyl]ethanesulfonamide 446N-[3-(1,5-dimethyl-6-oxopyridin-3- A A A C yl)-4-(oxan-3- yloxy)phenyl]methanesulfonamide 447 N-[4-(4,4-difluorocyclohexyl)oxy- A A A C3-(1,5-dimethyl-6-oxopyridin-3- yl)phenyl]methanesulfonamide 448N-[3-(1,5-dimethyl-6-oxopyridin-3- A A A C yl)-4-(oxan-3-yloxy)phenyl]ethanesulfonamide 449 N-[4-(4,4-difluorocyclohexyl)oxy- A AA C 3-(1,5-dimethyl-6-oxopyridin-3- yl)phenyl] ethanesulfonamide 4505-[2-(cyclopropylmethoxy)-5- A A A C ethylsulfonylphenyl]-1,3-dimethylpyridin-2-one 451 N-[4-(2,4-difluorophenoxy)-3-(5- A ND A Chydroxy-1-methyl-6-oxopyridin-3- yl)phenyl]ethanesulfonamide 4524-(cyclopropylmethylamino)-3- B ND B C (1,5-dimethyl-6-oxopyridin-3- yl)benzenesulfonamide 453 4-(cyclopropylmethylamino)-3-(1- C C C Cmethyl-6-oxopyridin-3- yl)benzenesulfonamide 4545-[2-(2,4-difluorophenoxy)-5- A A A C (methylsulfonylmethyl)phenyl]-1,4-dimethylpyridin-2-one 455 5-[2-(2,4-difluorophenoxy)-5- A A A C(methylsulfonylmethyl)phenyl]-1,3- dimethylpyridin-2-one 4565-(2-ethoxy-5- A ethylsulfonylphenyl)-1-(²H₃)methyl-4-methylpyridin-2-one 457 5-[2-(cyclopropylmethoxy)-5- A Aethylsulfonylphenyl]-1- (²H₃)methyl-4-methylpyridin-2-one 4585-(2-ethoxy-5- A ethylsulfonylphenyl)-1,4- dimethylpyridin-2-one 4595-[2-(cyclobutylmethoxy)-5- A A A C methylsulfonylphenyl]-1,3-dimethylpyridin-2-one 460 5-[2-(cyclobutylmethoxy)-5- Amethylsulfonylphenyl]-1- methylpyridin-2-one 461 5-(5-ethylsulfonyl-2- Bmethoxyphenyl)-3-hydroxy-1- methylpyridin-2-one 4625-[2-(cyclopropylmethylamino)-5- A A A C methylsulfonylphenyl]-1,3-dimethylpyridin-2-one 463 N-[4-(2,4-difluorophenoxy)-3-[5- A A A C(dimethylamino)-1-methyl-6- oxopyridin-3- yl]phenyl]methanesulfonamide464 N-[4-(2,4-difluorophenoxy)-3-[5- A A A C (dimethylamino)-1-methyl-6-oxopyridin-3- yl]phenyl]ethanesulfonamide 4655-[2-(cyclopropylmethylamino)-5- A A A C ethylsulfonylphenyl]-1,3-dimethylpyridin-2-one 466 5-[2-(cyclopropylmethoxy)-5- A A A Cethylsulfonylphenyl]-1,4- dimethylpyridin-2-one 467N-[3-(5-hydroxy-1-methyl-6- B C C C oxopyridin-3-yl)phenyl]methanesulfonamide 468 5-[2-(cyclopropylmethylamino)-5- A C BC methylsulfonylphenyl]-1- methylpyridin-2-one 4693-(dimethylamino)-5-(2-ethoxy-5- A A A C ethylsulfonylphenyl)-1-methylpyridin-2-one 470 5-[2-(2,4-difluorophenoxy)-5- A A A B(methylsulfonylmethyl)phenyl]-1- methylpyridin-2-one 471N-[3-(1-methyl-6-oxo-5- C phenylmethoxypyridin-3-yl)phenyl]methanesulfonamide 472 N-[4-(2,4-difluorophenoxy)-3-(1,5- A AA C dimethyl-6-oxopyridin-3- yl)phenyl]ethanesulfonamide 4735-[2-(cyclopropylmethylamino)-5- A B A C ethylsulfonylphenyl]-1-methylpyridin-2-one 474 5-[2-(cyclopropylmethoxy)-5- A A A Cmethylsulfonylphenyl]-3- (dimethylamino)-1-methylpyridin- 2-one 4755-[4-fluoro-2-methoxy-5- B (methylsulfonylmethyl)phenyl]-1-methylpyridin-2-one 476 5-[2-(cyclopropylmethoxy)-5- A B A Cmethylsulfonylphenyl]-1,3- dimethylpyridin-2-one 4775-[2-(cyclopropylmethoxy)-5- A B A C methylsulfonylphenyl]-1,4-dimethylpyridin-2-one 478 N-[6-[3- C (methanesulfonamido)phenyl]-4-methyl-3-oxopyrazin-2- yl]acetamide 479N-[3-(1,4-dimethyl-6-oxopyridazin- C 3-yl)phenyl]ethanesulfonamide 480N-[3-(1,5-dimethyl-6-oxopyridazin- B 3-yl)phenyl]ethanesulfonamide 481N-[5-[3- C (methanesulfonamido)phenyl]-1- methyl-2-oxopyridin-3-yl]propanamide 482 N-[5-[3- C (methanesulfonamido)phenyl]-1-methyl-2-oxopyridin-3- yl]acetamide 483 1-cyclobutyl-5-[2- A(cyclopropylmethoxy)-5- methylsulfonylphenyl]-3- methylpyridin-2-one 484N-[3-(1-cyclobutyl-5-methyl-6- A oxopyridin-3-yl)-4-(2,4-difluorophenoxy)phenyl]methane- sulfonamide 485 1-benzyl-5-[2- B(cyclopropylmethoxy)-5- methylsulfonylphenyl]-3- methylpyridin-2-one 4861,3-dimethyl-5-(2-methyl-5- B C B C methylsulfonyl-2,3-dihydro-1-benzofuran-7-yl)pyridin-2-one 487 4-[5-(ethylsulfonylmethyl)-2- A A A C(2,2,2-trifluoroethoxy)phenyl]-2- methylisoquinolin-1-one 4882-methyl-4-[5- A A A C (methylsulfonylmethyl)-2-(2,2,2- trifluoroethoxy)phenyl]isoquinolin- 1-one 489 1,3-dimethyl-5-(7-methylsulfonyl- B2,3-dihydro-1,4-benzodioxin-5- yl)pyridin-2-one 490N-[2-ethyl-8-(2-methyl-1- A oxoisoquinolin-4-yl)-3,4-dihydro-2H-chromen-6- yl] methanesulfonamide 491 N-[2-ethyl-8-(2-methyl-1- Aoxoisoquinolin-4-yl)-3,4-dihydro- 2H-chromen-6- yl]ethanesulfonamide 492N-[8-(1,5-dimethyl-6-oxopyridin-3- A yl)-2-ethyl-3,4-dihydro-2H-chromen-6-yl] ethanesulfonamide 493 4-(2-cyclopropyl-5-methylsulfonyl- A2,3-dihydro-1-benzofuran-7-yl)-2- methylisoquinolin-1-one 4944-(2-ethyl-5-methylsulfonyl-2,3- A B dihydro-1-benzofuran-7-yl)-2-methylisoquinolin-1-one 495 N-[7-(1,5-dimethyl-6-oxopyridin-3- Ayl)-2-propyl-2,3-dihydro-1- benzofuran-5-yl] ethanesulfonamide 496N-[2-cyclopropyl-7-(1,5-dimethyl- A A 6-oxopyridin-3-yl)-2,3-dihydro-1-benzofuran-5-yl]ethanesulfonamide 497 4-[3-(methoxymethyl)-7- A B B Cmethylsulfonyl-2,3-dihydro-1,4- benzodioxin-5-yl]-2-methylisoquinolin-1-one 498 5-[3-(methoxymethyl)-7- A C B Cmethylsulfonyl-2,3-dihydro-1,4- benzodioxin-5-yl]-1,3-dimethylpyridin-2-one 499 4-[3-(methoxymethyl)-7- Amethylsulfonyl-2,3-dihydro-1,4- benzodioxin-5-yl]-2-methylisoquinolin-1-one 500 5-[3-(methoxymethyl)-7- Amethylsulfonyl-2,3-dihydro-1,4- benzodioxin-5-yl]-1,3-dimethylpyridin-2-one 501 4-[2-(methoxymethyl)-7- A B B Cmethylsulfonyl-2,3-dihydro-1,4- benzodioxin-5-yl]-2-methylisoquinolin-1-one 502 5-[2-(methoxymethyl)-7- Amethylsulfonyl-2,3-dihydro-1,4- benzodioxin-5-yl]-1,3-dimethylpyridin-2-one 503 4-[2-(methoxymethyl)-7- Amethylsulfonyl-2,3-dihydro-1,4- benzodioxin-5-yl]-2-methylisoquinolin-1-one 504 4-[2-(cyclopropylmethoxy)-5- A Amethylsulfonylphenyl]-2-methyl- 6,7-dihydro-5H-cyclopenta[c]pyridin-1-one 505 4-[2-(cyclopropylmethoxy)-5- Aethylsulfonylphenyl]-2-methyl-6,7- dihydro-5H-cyclopenta[c]pyridin-1-one 506 N-[4-(2,4-difluorophenoxy)-3-(2- A methyl-1-oxo-6,7-dihydro-5H-cyclopenta[c]pyridin-4- yl)phenyl]methanesulfonamide 507N-[4-(2,4-difluorophenoxy)-3-(2- A methyl-1-oxo-6,7-dihydro-5H-cyclopenta[c] pyridin-4- yl)phenyl]ethanesulfonamide 508 5-(5-butyl-2- Amethylsulfonylpyrimidin-4-yl)-3- methyl-1-propan-2-ylpyridin-2-one 509N-[5-(2,4-difluorophenoxy)-4-(5- A A methyl-6-oxo-1-propan-2-ylpyridin-3-yl)pyrimidin-2- yl]ethanesulfonamide 5105-[5-(2,4-difluorophenoxy)-2- B methylsulfonylpyrimidin-4-yl]-3-methyl-1-propan-2-ylpyridin-2-one 511 N-[5-butyl-4-(5-methyl-6-oxo-1- AA propan-2-ylpyridin-3-yl)pyrimidin- 2-yl] ethanesulfonamide 512N-[5-butyl-4-(1-methyl-6-oxo-5- A A propan-2-ylpyridin-3-yl)pyrimidin-2-yl] ethanesulfonamide 513 5-(5-butyl-2- Amethylsulfonylpyrimidin-4-yl)-1- methyl-3-propan-2-ylpyridin-2-one 514N-[5-(2,4-difluorophenoxy)-4- A (1-methyl-6-oxo-5-propan-2-ylpyridin-3-yl) pyrimidin-2- yl]ethanesulfonamide Note: IC₅₀ data aredesignated within the following ranges: A: ≦0.5 μM; B: >0.5 μM to ≦5.0μM; C: >5.0 μM

Example 3: In Vivo Xenograph Study—Antitumor Efficacy in XenograftModels of NUT Midline Carcinoma (NMC)

Xenograft models of NMC in mice are used in this study. Matched cohortsof mice with established tumors are randomized to treatment with a testcompound or vehicle, administered by daily intraperitoneal injection.Before randomization and after 4 days of therapy, mice are evaluated by¹⁸F-fluorodeoxyglucose (FDG)-PET imaging. Tumor-volume measurements arealso made, as are measures of toxicity or weight loss. Tumors areobtained and sectioned and immunohisto-chemically examined for theBRD4-NUT oncoprotein, cell spreading, keratin expression, nuclear Ki67,and TUNEL staining. Paired samples from treated and untreated mice areprepared and analyzed using standardized protocols and commerciallyavailable software (i.e., ImageScopt; Aperio Technologies).

Example 4: In Vivo Xenograph Study—Antitumor Efficacy in XenograftModels of MCF-7 Breast Cancer

Time release pellets containing 0.72 mg 1743 Estradiol aresubcutaneously implanted into nu/nu mice. MCF-7 cells are grown in RPMIcontaining 10% FBS at 5% CO₂, 37° C. Cells are spun down andre-suspended in 50% RPMI (serum free) and 50% Matrigel at 1×10⁷cells/mL. MCF-7 cells are subcutaneously injected (100 μL/animal) on theright flank 2-3 days post pellet implantation and tumor volume(length×width²/2) is monitored bi-weekly. When tumors reach an averagevolume of ˜200 mm³ animals are randomized and treatment is started.Animals are treated with a test compound or vehicle daily for 4 weeks.Tumor volume and body weight are monitored bi-weekly throughout thestudy. At the conclusion of the treatment period, plasma and tumorsamples are taken for pharmacokinetic and pharmacodynamic analyses,respectively.

Example 5: In Vivo Xenograph Study—Antitumor Efficacy in Xenograft Modelof Raji Human Burkitts Lymphoma Model

Procedure:

Female SCID CB17 mice (6-8 weeks old, Charles River Laboratories) wereinoculated subcutaneously in the right flank region with Raji cells (at3.5×106 cells/mouse) and the tumor was allowed to grow to approximately150 mm³. Mice were then randomized into treatment cohorts (N=8) andtreated orally once daily with vehicle control or test compound for 21days. Test compound was administered as a suspension in 1% Tween 80, 40%PEG400 and either: 59% of 0.5% HPMC, or 9% DMSO+50% of 0.5% HPMC. Tumorslength and width were measured in millimeters three times per week.Tumor volumes were calculated by the formula V=L×W²/2. Tumor growthinhibition (TGI) was calculated with the formula:

TGI=100−(median tumor volume of treatment group/median tumor volume ofvehicle control group)×100

TGI measurements were performed until the volume of a tumor in thecontrol group reached 3,000 mm³. Statistical analysis was performedusing 2-tailed T-test. P values <0.05 were considered as statisticallysignificant.

Preliminary Results:

Seven compounds from Table 1 were selected and administered at dosesranging from 5 mg/kg to 50 mg/kg. TGI was determined to range from 42%to 80%. Results are preliminary and do not reflect optimized dosingschedules.

III. Preparation of Pharmaceutical Dosage Forms Example 1: Oral Tablet

A tablet is prepared by mixing 48% by weight of a compound of Formula(I), or a pharmaceutically acceptable salt thereof, 45% by weight ofmicrocrystalline cellulose, 5% by weight of low-substitutedhydroxypropyl cellulose, and 2% by weight of magnesium stearate. Tabletsare prepared by direct compression. The total weight of the compressedtablets is maintained at 250-500 mg.

We claim:
 1. A compound of Formula (I)

wherein the compound of Formula (I) includes a pharmaceuticallyacceptable salt thereof, wherein: R² is selected from CH₃, CH₂CH₃,CH₂CF₃, CH₂F, CHF₂, CF₃, CH₂D, CHD₂, or CD₃; X5 is N or C—R⁵, wherein R⁵is hydrogen, halogen, —OH, —CN, —OR⁶¹, —NHR⁶¹, —N(R⁶¹)₂, alkyl,cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,heterocyclylalkyl, heteroaryl, or heteroarylalkyl, wherein each R⁶¹ isindependently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl,aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, orheteroarylalkyl; X6 is N or C—R⁶, wherein R⁶ is hydrogen, halogen, —OH,—CN, —OR⁶¹, —NHR⁶¹, —N(R⁶¹)₂, alkyl, cycloalkyl, cycloalkylalkyl, aryl,aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, orheteroarylalkyl, wherein each R⁶¹ is independently selected from alkyl,cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,heterocyclylalkyl, heteroaryl, or heteroarylalkyl; X7 is N or C—R⁷,wherein R⁷ is hydrogen, halogen, —OH, —CN, —OR⁶¹, —NHR⁶¹, —N(R⁶¹)₂,alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,heterocyclylalkyl, heteroaryl, or heteroarylalkyl, wherein each R⁶¹ isindependently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl,aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, orheteroarylalkyl; X8 is N or C—R⁸, wherein R⁸ is hydrogen, halogen, oralkyl; wherein no more than two of X5, X6, X7, or X8 may be N; R^(A) is

 wherein X2 is N or C—R¹², wherein R¹² is hydrogen, halogen, alkyl, oralkoxy; R¹³ is —Y—Z, wherein Y is selected from a bond, —CH₂—, or—CH(C₁-C₄ alkyl)-; and Z is selected from —SO₂R²¹, —N(R²²)SO₂R²¹,—SO₂N(R²²)₂, —N(R²²)SO₂N(R²²)₂, —CON(R²²)₂, —N(R²²)CO₂R²¹,—N(R²²)CON(R²²)₂, —N(R²²)COR²¹, —COR²¹, —OC(O)N(R²²)₂, —OSO₂N(R²²)₂, or—N(R²²)SO₃R²¹, wherein each R²¹ is independently selected from alkyl,cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,heterocyclylalkyl, heteroaryl, or heteroarylalkyl; and each R²² isindependently selected from hydrogen, alkyl, cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,heteroaryl, or heteroarylalkyl. X3 is N or C—R¹⁴, wherein R¹⁴ ishydrogen, halogen, —CN, alkyl, cycloalkyl, or alkoxy; X4 is N or C—R¹⁵,wherein R¹⁵ is hydrogen, halogen, alkyl, —CN, or alkoxy; and R¹⁶ ishydrogen, halogen, —N(H)COX, or —W—X, wherein W is a bond, —O—, —S—, or—NH—, and X is selected from alkyl, aryl, aralkyl, cycloalkyl,cycloalkylalkyl, alkynyl, cycloalkylalkynyl, heterocyclyl,heterocyclylalkyl, heteroaryl, or heteroarylalkyl.
 2. The compound ofclaim 1, having the structure of Formula (Ib),

wherein, R² is CH₃; X5 is C—H; X6 is C—R⁶, in which R⁶ is hydrogen orhalogen; X7 is C—R⁷, in which R⁷ is hydrogen or halogen; X8 is C—H; andR^(A) is

 in which X2 is C—H; R¹³ is —Y—Z, wherein Y is a bond or —CH₂—, and Z isselected from —SO₂R²¹, —N(R²²)SO₂R²¹, —SO₂N(R²²)₂, —N(R²²)SO₂N(R²²)₂,—CON(R²²)₂, —N(R²²)CO₂R²¹, —N(R²²)CON(R²²)₂, —N(R²²)COR²¹,—OC(O)N(R²²)₂, —OSO₂N(R²²)₂, or —N(R²²)SO₃R²¹, wherein each R²¹ isindependently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl,aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, orheteroarylalkyl, and each R²² is independently selected from hydrogen,alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,heterocyclylalkyl, heteroaryl, or heteroarylalkyl; X3 is C—R¹⁴, whereinR¹⁴ is hydrogen, halogen, C₁-C₃ alkyl, or C₁-C₃ alkoxy; X4 is C—R¹⁵,wherein R¹⁵ is hydrogen or halogen; and R¹⁶ is —W—X, wherein W is abond, —O—, —S—, or —NH—; and X is selected from alkyl, aryl, aralkyl,cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl,heteroaryl, or heteroarylalkyl.
 3. The compound of claim 2, wherein R⁶is halogen, and R⁷ is hydrogen.
 4. The compound of claim 2, wherein R⁶is hydrogen, and R⁷ is halogen.
 5. The compound, or a pharmaceuticallyacceptable salt thereof, of claim 2, wherein R⁶ is hydrogen, and R⁷ ishydrogen.
 6. The compound of claim 2, wherein Y is —CH₂—.
 7. Thecompound of claim 6, wherein Z is —SO₂R²¹ or —N(R²²)SO₂R²¹.
 8. Thecompound of claim 2, wherein Y is a bond.
 9. The compound of claim 8,wherein Z is —N(R²²)SO₂R²¹ or —N(R²²)SO₂N(R²²)₂.
 10. The compound ofclaim 8, wherein Z is —SO₂R²¹.
 11. The compound of claim 8, wherein Z is—SO₂N(R²²)₂.
 12. The compound of claim 10, wherein R²¹ is heterocyclyl,or heterocyclylalkyl.
 13. The compound of claim 9, wherein R²² ishydrogen or methyl.
 14. The compound of claim 11, wherein at least oneR²² is alkyl, cycloalkyl, or aralkyl.
 15. The compound of claim 10,wherein R²¹ is alkyl, cycloalkyl, or cycloalkylalkyl.
 16. The compoundof claim 15, wherein the alkyl is a C₁-C₄ alkyl.
 17. The compound ofclaim 2, wherein R¹⁴ is hydrogen and R¹⁵ is hydrogen.
 18. The compoundof claim 2, wherein W is a bond or —NH—.
 19. The compound of claim 2,wherein W is —O—.
 20. The compound of claim 18, wherein X is alkyl. 21.The compound of claim 19, wherein X is alkyl.
 22. The compound of claim18, wherein X is cycloalkylalkyl.
 23. The compound of claim 19, whereinX is cycloalkylalkyl.
 24. The compound of claim 18, wherein X is aryl.25. The compound of claim 19, wherein X is aryl.
 26. The compound ofclaim 16, wherein the C₁-C₄ alkyl is methyl.
 27. The compound of claim2, wherein Y is a bond, Z is —SO₂R²¹, W is —O—, and X is aryl orcycloalkylalkyl.
 28. A pharmaceutical composition comprising thecompound of claim 1 and a pharmaceutically acceptable excipient.
 29. Acompound, or a pharmaceutically acceptable salt thereof, selected from:N-[4-methyl-3-(2-methyl-1-oxoisoquinolin-4-yl)phenyl]methanesulfonamide;4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one;4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-6-fluoro-2-methylisoquinolin-1-one;4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-7-fluoro-2-methylisoquinolin-1-one;4-[2-(2,4-difluorophenoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one;N-[4-(2,4-difluorophenoxy)-3-(2-methyl-1-oxoisoquinolin-4-yl)phenyl]ethanesulfonamide;4-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-2-methylisoquinolin-1-one;4-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-6-fluoro-2-methylisoquinolin-1-one;2-methyl-4-[5-methylsulfonyl-2-(oxolan-3-yloxy)phenyl]isoquinolin-1-one;2-methyl-4-[5-methylsulfonyl-2-(oxan-4-yloxy)phenyl]isoquinolin-1-one;4-(2-ethoxy-5-methylsulfonylphenyl)-2-methylisoquinolin-1-one;2-methyl-4-(5-methylsulfonyl-2-propoxyphenyl)isoquinolin-1-one;2-methyl-4-[5-methylsulfonyl-2-(oxan-3-yloxy)phenyl]isoquinolin-1-one;4-[2-(trans-4-hydroxycyclohexyl)oxy-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one;4-[5-ethylsulfonyl-2-(trans-4-hydroxycyclohexyl)oxyphenyl]-2-methylisoquinolin-1-one;4-[2-(trans-4-aminocyclohexyl)oxy-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one;4-[2-(cis-4-aminocyclohexyl)oxy-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one;4-(2-but-2-ynoxy-5-methylsulfonylphenyl)-2-methylisoquinolin-1-one;4-(2-but-2-ynoxy-5-ethylsulfonylphenyl)-2-methylisoquinolin-1-one;6-fluoro-4-[2-(trans-4-hydroxycyclohexyl)oxy-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one;7-fluoro-4-[2-(trans-4-hydroxycyclohexyl)oxy-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one;4-[5-ethylsulfonyl-2-(trans-4-hydroxycyclohexyl)oxyphenyl]-6-fluoro-2-methylisoquinolin-1-one;4-[5-ethylsulfonyl-2-(trans-4-hydroxycyclohexyl)oxyphenyl]-7-fluoro-2-methylisoquinolin-1-one;2-methyl-4-[5-methylsulfonyl-2-(oxolan-3-ylamino)phenyl]isoquinolin-1-one;2-methyl-4-[5-methylsulfonyl-2-(oxan-4-ylamino)phenyl]isoquinolin-1-one;4-[2-[(trans-4-hydroxycyclohexyl)amino]-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one;4-[2-(cyclopropylmethylamino)-5-ethylsulfonylphenyl]-2-methylisoquinolin-1-one;4-[2-(cyclopropylmethylamino)-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one;4-[2-(cyclopropylmethylamino)-5-ethylsulfonylphenyl]-7-fluoro-2-methylisoquinolin-1-one;4-[2-(cyclopropylmethylamino)-5-methylsulfonylphenyl]-7-fluoro-2-methylisoquinolin-1-one;4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methyl-6-(trifluoromethyl)isoquinolin-1-one;4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-6-methoxy-2-methylisoquinolin-1-one;[4-(cyclopropylmethoxy)-3-(2-methyl-1-oxoisoquinolin-4-yl)phenyl]sulfamate;N-[2-(2-methyl-1-oxoisoquinolin-4-yl)-4-methylsulfonylphenyl]-cyclopropanecarboxamide;N-[2-(2-methyl-1-oxoisoquinolin-4-yl)-4-methylsulfonylphenyl]propanamide;N-[2-(2-methyl-1-oxoisoquinolin-4-yl)-4-methylsulfonylphenyl]acetamide;2-methyl-4-(5-methylsulfonyl-2-propylphenyl)isoquinolin-1-one;4-(2-ethyl-5-methylsulfonylphenyl)-2-methylisoquinolin-1-one;4-(2-butyl-5-methylsulfonylphenyl)-2-methylisoquinolin-1-one;4-[2-(2-cyclopropylethyl)-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one;4-[2-(cyclopropylmethoxy)-5-propan-2-ylsulfonylphenyl]-2-methylisoquinolin-1-one;4-[2-(cyclopropylmethoxy)-5-propan-2-ylsulfonylphenyl]-6-methoxy-2-methylisoquinolin-1-one;4-[5-(ethylsulfonylmethyl)-2-(2,2,2-trifluoroethoxy)phenyl]-2-methylisoquinolin-1-one;and2-methyl-4-[5-(methylsulfonylmethyl)-2-(2,2,2-trifluoroethoxy)phenyl]isoquinolin-1-one.30. A pharmaceutical composition comprising a compound of claim 29, orthe pharmaceutical salt thereof, and a pharmaceutically acceptableexcipient.
 31. A compound of Formula (IIa)

wherein the compound of Formula (IIa) includes a pharmaceuticallyacceptable salt thereof, and wherein: R² is CH₃, CH₂CH₃, CH₂CF₃, CH₂F,CHF₂, CF₃, CH₂D, CHD₂, or CD₃; X6 is C—H; X5 is C—R⁵, wherein R⁵ ishydrogen, halogen, —OH, —CN, —OR⁶¹, —NHR⁶¹, —N(R⁶¹)₂, alkyl, cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,heteroaryl, or heteroarylalkyl, wherein each R⁶¹ is independentlyselected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl,heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; R⁶ ishydrogen, halogen, —OH, —CN, alkyl, cycloalkyl, cycloalkylalkyl, amino,alkylamino, dialkylamino, cycloalkylalkylamino, alkoxy, orcycloalkylalkoxy; and R^(A) is

 wherein X2 is N; R¹³ is —Y—Z, wherein Y is a bond or —CH₂—, and Z isselected from —SO₂R²¹, —N(R²²)SO₂R²¹, —SO₂N(R²²)₂, —N(R²²)SO₂N(R²²)₂,—CON(R²²)₂, —N(R²²)CO₂R²¹, —N(R²²)CON(R²²)₂, —N(R²²)COR²¹,—OC(O)N(R²²)₂, —OSO₂N(R²²)₂, or —N(R²²)SO₃R²¹, in which each R²¹ isindependently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl,aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, orheteroarylalkyl; and each R²² is independently selected from hydrogen,alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,heterocyclylalkyl, heteroaryl, or heteroarylalkyl; X3 is N; X4 is C—R¹⁵,wherein R¹⁵ is hydrogen, halogen, —CN, alkyl, or alkoxy; and R¹⁶ ishydrogen, halogen, or —W—X, wherein W is a bond, —O—, —S—, or —NH—, andX is selected from alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl.
 32. Thecompound of claim 31, wherein R⁵ is hydrogen, halogen, —OR⁶¹, or alkyl;R⁶¹ is alkyl; and R⁶ is hydrogen, halogen, alkyl, alkoxy.
 33. Thecompound of claim 32, having the structure of Formula (IIb)

wherein: R² is CH₃; X6 is C—H; X5 is C—R⁵, in which R⁵ is hydrogen; R⁶is halogen or alkyl; R^(A) is

 in which X2 is N; R¹³ is —Y—Z, wherein Y is selected from a bond, or—CH₂—, and Z is selected from —SO₂R²¹, —N(R²²)SO₂R²¹, —SO₂N(R²²)₂,—N(R²²)SO₂N(R²²)₂, —CON(R²²)₂, —N(R²²)CO₂R²¹, —N(R²²)CON(R²²)₂,—N(R²²)COR²¹, —OC(O)N(R²²)₂, —OSO₂N(R²²)₂, or —N(R²²)SO₃R²¹, whereineach R²¹ is independently selected from alkyl, cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,heteroaryl, or heteroarylalkyl; and each R²² is independently selectedfrom hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl,heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; X3 isN; X4 is C—R¹⁵, wherein R¹⁵ is hydrogen, halogen, —CN, alkyl, or alkoxy;and R¹⁶ is —W—X, wherein W is a bond, —O—, —S—, or —NH—, and X isselected from alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl.
 34. Thecompound of claim 32 wherein R⁶ is halogen.
 35. The compound of claim 32wherein R⁶ is alkyl.
 36. The compound of claim 32, wherein R⁶ is C₁-C₃alkyl.
 37. The compound of claim 32, wherein R⁶ is methyl.
 38. Thecompound of claim 32, wherein Y is a bond.
 39. The compound of claim 32,wherein Y is a —CH₂—.
 40. The compound of claim 32, wherein Z is—SO₂R²¹.
 41. The compound of claim 32, wherein Z is —N(R²²)SO₂R²¹. 42.The compound of claim 32, wherein R²¹ is alkyl, cycloalkyl, orcycloalkylalkyl.
 43. The compound of claim 32, wherein R²¹ is alkyl. 44.The compound of claim 32, wherein R²¹ is C₁-C₂ alkyl.
 45. The compoundof claim 32, wherein R²² is hydrogen.
 46. The compound of claim 32,wherein W is —O—.
 47. The compound of claim 32, wherein W is a bond. 48.The compound of claim 32, wherein X is alkyl.
 49. The compound of claim32, wherein X is aryl.
 50. The compound of claim 32, wherein X iscycloalkylalkyl.
 51. The compound of claim 32, wherein W is —O— and X isaryl.
 52. The compound of claim 32, wherein W is —O— and X iscycloalkylalkyl.
 53. The compound of claim 32, wherein W is a bond and Xis alkyl.
 54. The compound of claim 32, wherein W is a bond and X iscycloalkylalkyl.
 55. The compound of claim 32, having the structure:


56. The compound of claim 32, having the structure:


57. The compound of claim 32, having the structure:


58. The compound of claim 32, having the structure:


59. The compound of claim 32, having the structure:


60. A pharmaceutical composition comprising a pharmaceuticallyacceptable excipient and the compound of claim
 31. 61. A pharmaceuticalcomposition comprising a pharmaceutically acceptable excipient and thecompound of claim
 33. 62. A compound of Formula (XXIV)

wherein the compound of Formula (XXIV) includes a pharmaceuticallyacceptable salt thereof, and wherein: R¹³ is —Y—Z, wherein Y is a bondor —CH₂—; and Z is selected from —SO₂R²¹, —N(R²²)SO₂R²¹, —SO₂N(R²²)₂,—N(R²²)SO₂N(R²²)₂, —CON(R²²)₂, —N(R²²)₂, —N(R²²)CO₂R²¹,—N(R²²)CON(R²²)₂, —N(R²²)COR²¹, —OC(O)N(R²²)₂, —OSO₂N(R²²)₂, —NSO₂R²¹,—OR²¹, —COR²¹, or —N(R²²)SO₃R²¹, wherein each R²¹ is independentlyselected from optionally substituted alkyl, cycloalkyl, cycloalkylalkyl,aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, orheteroarylalkyl, and each R²² is independently selected from hydrogen oroptionally substituted alkyl, cycloalkyl, cycloalkylalkyl, aryl,aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, orheteroarylalkyl; R¹⁴ is hydrogen, halogen, or optionally substitutedC₁-C₃ alkyl or C₁-C₃ alkoxy; R¹⁵ is hydrogen, halogen, or U—V, wherein Uis a bond, —O—, or C₁-C₃ alkyl; and Vis —CN or optionally substitutedalkyl, alkynyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; R¹⁶ ishydrogen; and R^(B) is

 wherein R² is CH₃; X5 is C—H; X6 is C—R⁷, in which R⁷ is hydrogen orhalogen; X7 is C—R⁸, in which R⁸ is hydrogen or halogen; and X8 is C—H;or R^(B) is

 wherein X5 is C—R⁵, in which R⁵ is hydrogen or halogen; X6 is C—H; R²is CH₃; and R⁶ is hydrogen, halogen, or optionally substituted alkyl oralkoxy; or R^(B) is

 wherein Ring B is an optionally substituted 5-membered heteroaryl ringcontaining at least one oxygen or sulfur atom; X1 is C—H; and R² is CH₃.63. The compound of claim 62, wherein Y is —CH₂—.
 64. The compound ofclaim 62, wherein Y is a bond.
 65. The compound of claim 62, wherein Zis —SO₂R²¹, —NSO₂R²¹, —N(R²²)SO₂R²¹, or —N(R²²)₂.
 66. The compound ofclaim 62, wherein Z is —SO₂R²¹ or —N(R²²)SO₂R²¹.
 67. The compound ofclaim 62, wherein Z is —SO₂R²¹.
 68. The compound of claim 62, wherein Zis —NSO₂R²¹.
 69. The compound of claim 62, wherein Z is —N(R²²)SO₂R²¹.70. The compound of claim 62, wherein R²¹ is heterocyclyl orheterocyclylalkyl.
 71. The compound of claim 62, wherein R²¹ is alkyl,cycloalkyl, or cycloalkylalkyl.
 72. The compound of claim 62, whereinR²¹ is alkyl, and the alkyl is C₁-C₄ alkyl.
 73. The compound of claim62, wherein R²² is hydrogen or methyl.
 74. The compound of claim 62,wherein R²² is alkyl, cycloalkyl, or aralkyl.
 75. The compound of claim62, wherein
 76. The compound of claim 62, wherein R¹⁴ is hydrogen. 77.The compound of claim 62, wherein R¹⁵ is hydrogen.
 78. The compound ofclaim 62, wherein U is a bond.
 79. The compound of claim 62, wherein Uis —O—.
 80. The compound of claim 62, wherein U is —CH₂—.
 81. Thecompound of claim 62, wherein V is alkyl.
 83. The compound of claim 62,wherein V is aryl.
 84. The compound of claim 62, wherein V is aralkyl.85. The compound of claim 62, wherein V is cylcoalkylalkyl.
 86. Thecompound of claim 62, wherein V is heterocyclylalkyl.
 87. The compoundof claim 62, wherein V is heteroaryl.
 88. The compound of claim 62,wherein V is heteroarylalkyl.
 89. The compound of claim 62, wherein V isalkynyl.
 90. The compound of claim 62, wherein R¹⁴ is hydrogen; Y is abond; Z is —NSO₂R²¹ or SO₂R²¹; U is —O—; and V is substituted aryl,heteroaryl, or aralkyl.
 91. The compound of claim 76, wherein R^(B) is


92. The compound of claim 91, wherein X6 is C—R⁷ and R⁷ is substitutedaryl.
 93. The compound of claim 62, wherein Y is a bond, Z is—N(R²²)SO₂R²¹, U is —O—, and V is aryl, aralkyl, or cycloalkylalkyl. 94.The compound of claim 62, wherein Y is a bond, Z is —SO₂R²¹, U is —O—,and V is aryl, aralkyl, or cycloalkylalkyl.
 95. The compound of claim62, wherein R^(B) is


96. The compound of claim 62, wherein R⁷ is halogen and R⁸ is hydrogen.97. The compound of claim 62, wherein R⁷ is hydrogen and R⁸ is halogen.98. The compound of claim 62, wherein R⁷ is hydrogen and R⁸ is hydrogen.99. The compound of claim 62, wherein R^(B) is


100. The compound of claim 99, wherein R^(B) is

wherein X5 is C—R⁵ in which R⁵ is hydrogen or halogen, and R⁶ ishydrogen, halogen, alkyl, or alkoxy.
 101. The compound of claim 62,wherein R⁵ is hydrogen, and R⁶ is alkyl.
 102. The compound of claim 62,wherein R⁶ is methyl.
 103. The compound of claim 62, wherein R^(B) is


104. The compound of claim 103, wherein Ring B is an optionallysubstituted 5-membered heteroaryl ring containing one oxygen.
 105. Thecompound of claim 103, wherein R^(B) is

wherein Ring B is an optionally substituted heterocyclyl ring containingat least one oxygen and at least one sulfur atom.
 106. The compound ofclaim 95, wherein R^(B) is


107. The compound of claim 106, wherein X6 is C—R⁷ and R⁷ is substitutedhydrogen or halogen, and X7 is C—R⁸, wherein R⁸ is hydrogen or halogen.108. A pharmaceutical compound comprising the compound of claim 62 andat least one pharmaceutical excipient.
 107. A method for inhibiting ahistone-demethylase enzyme comprising contacting a histone demethylaseenzyme with a compound of Formula XXIV

wherein a compound of Formula XXIV includes pharmaceutically acceptablesalts thereof, wherein: R¹³ is —Y—Z, wherein Y is a bond, hydrogen, orCH₃, and Z is selected from —SO₂R²¹, —N(R²²)SO₂R²¹, —SO₂N(R²²)₂,—N(R²²)SO₂N(R²²)₂, —CON(R²²)₂, —N(R²²)₂, —N(R₂₂)CO₂R²¹,—N(R²²)CON(R²²)₂, —N(R²²)COR²¹, —OC(O)N(R²²)₂, —OSO₂N(R²²)₂, —NSO₂R²¹,—OR²¹, —COR²¹, or —N(R²²)SO₃R²¹, wherein each R²¹ is independentlyselected from optionally substituted alkyl, cycloalkyl, cycloalkylalkyl,aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, orheteroarylalkyl, and each R²² is independently selected from hydrogen oroptionally substituted alkyl, cycloalkyl, cycloalkylalkyl, aryl,aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, orheteroarylalkyl; R¹⁴ is hydrogen, halogen, or optionally substitutedC₁-C₃ alkyl, or C₁-C₃ alkoxy; R¹⁵ is hydrogen, halogen or U—V, wherein Uis a bond, —O—, or C₁-C₃ alkyl, and V is —CN or optionally substitutedalkyl, alkynyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; andR^(B) is

 wherein R² is CH₃; X5 is C—H; X6 is C—R⁷, wherein R⁷ is hydrogen,halogen, or optionally substituted aryl; X7 is C—R⁸, wherein R⁸ ishydrogen, halogen, or obtionally substituted aryl; X8 is C—H; or R^(B)is

 wherein X5 is C—R⁵, wherein R⁵ is hydrogen or halogen, X6 is C—H, R² isCH₃, and R⁶ is hydrogen, halogen, or optionally substituted alkyl oralkoxy; or R^(B) is

 wherein Ring B is an optionally substituted 5-membered heteroaryl ringcontaining at least one oxygen or sulfur atom; X1 is C—H; and R² is CH₃.108. The method of claim 107, wherein R¹⁴ is hydrogen.
 109. The methodof claim 107, wherein R¹⁵ is hydrogen.
 110. The method of claim 107,wherein Y is a bond.
 111. The method of claim 107, wherein R²¹ is alkyl,and the alkyl is C₁-C₄ alkyl.
 112. The method of claim 107, wherein Z is—SO₂R²¹, —NSO₂R²¹, —N(R²²)SO₂R²¹, or —N(R²²)₂.
 113. The method of claim108, wherein Z is —SO₂R²¹ or —N(R²²)SO₂R²¹.
 114. The method of claim113, wherein R¹⁵ is hydrogen, and Y is a bond.
 115. The method of claim114, wherein R²¹ is C₁-C₄ alkyl.
 116. The method of claim 115, whereinR²² is H.
 117. The method of claim 115, wherein U is —O—.
 118. Themethod of claim 117, wherein V is substituted aryl or aralkyl.
 119. Themethod of claim 107, wherein R¹⁴ is hydrogen; Y is a bond; Z is —NSO₂R²¹or SO₂R²¹; U is —O—; and V is substituted aryl, heteroaryl, or aralkyl.120. The method of claim 119, wherein V is oaryl substituted withhalogen, C₁-C₄ alkyl, or haloalkoxy.
 121. The method of claim 108,wherein R^(B) is


122. The method of claim 121, wherein X6 is C—R⁷ and R⁷ is substitutedaryl.
 123. A method of treating cancer comprising administering to apatient a therapeutically effective dose of a pharmaceutical compoundcomprising the compound of claim 62.